Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 12/2016

01-12-2016 | Review

Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms

Authors: Huiping Shi, Weili Zhang, Qiaoming Zhi, Min Jiang

Published in: Tumor Biology | Issue 12/2016

Login to get access

Abstract

In the era of new and mostly effective molecular targeted therapies, human epidermal growth factor receptor 2 positive (HER2+) cancers are still intractable diseases. Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor, has greatly improved breast cancer prognosis in recent years after the initial introduction of trastuzumab (Herceptin). However, clinical evidence indicates the existence of both primary unresponsiveness and secondary lapatinib resistance, which leads to the failure of this agent in HER2+ cancer patients. It remains a major clinical challenge to target the oncogenic pathways with drugs having low resistance. Multiple pathways are involved in the occurrence of lapatinib resistance, including the pathways of receptor tyrosine kinase, non-receptor tyrosine kinase, autophagy, apoptosis, microRNA, cancer stem cell, tumor metabolism, cell cycle, and heat shock protein. Moreover, understanding the relationship among these mechanisms may contribute to future tumor combination therapies. Therefore, it is of urgent necessity to elucidate the precise mechanisms of lapatinib resistance and improve the therapeutic use of this agent in clinic. The present review, in the hope of providing further scientific support for molecular targeted therapies in HER2+ cancers, discusses about the latest findings and new concepts on molecular mechanisms underlying lapatinib resistance.
Literature
1.
Cameron DA, Stein S. Drug insight: intracellular inhibitors of her2--clinical development of lapatinib in breast cancer. Nat Clin Pract Oncol. 2008;5:512–20.PubMedCrossRef
2.
Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for her2-positive advanced breast cancer. N Engl J Med. 2006;355:2733–43.PubMedCrossRef
3.
Kim JW, Kim HP, Im SA, Kang S, Hur HS, Yoon YK, Oh DY, Kim JH, Lee DS, Kim TY, Bang YJ. The growth inhibitory effect of lapatinib, a dual inhibitor of egfr and her2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett. 2008;272:296–306.PubMedCrossRef
4.
Kim HP, Yoon YK, Kim JW, Han SW, Hur HS, Park J, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY. Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2. PLoS One. 2009;4:e5933.PubMedPubMedCentralCrossRef
5.
Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, Oliva C, Stein S, Gagnon R, Arbushites M, Koehler MT. HER-2 gene amplification, HER-2 and epidermal growth factor receptor mrna and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res. 2008;14:7861–70.PubMedCrossRef
6.
Nahta R, Shabaya S, Ozbay T, Rowe DL. Personalizing HER2-targeted therapy in metastatic breast cancer beyond HER2 status: what we have learned from clinical specimens. Curr Pharmacogenomics Person Med. 2009;7:263–74.PubMedPubMedCentralCrossRef
7.
Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of lapatinib alone or in combination with trastuzumab in women with ERBB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124–30.PubMedCrossRef
8.
Blackwell KL, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, Maltzman JD, Forster JK, Rubin SD, Stein SH, Burstein HJ. Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol. 2009;20:1026–31.PubMedCrossRef
9.
Iqbal S, Goldman B, Fenoglio-Preiser CM, Lenz HJ, Zhang W, Danenberg KD, Shibata SI, Blanke CD. Southwest oncology group study s0413: a phase II trial of lapatinib (gw572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol. 2011;22:2610–5.PubMedPubMedCentralCrossRef
10.
Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–16.PubMedCrossRef
11.
Eccles SA. The role of c-ERBB-2/HER2/neu in breast cancer progression and metastasis. J Mammary Gland Biol Neoplasia. 2001;6:393–406.PubMedCrossRef
12.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–82.PubMedCrossRef
13.
Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J, Ullrich A, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12.PubMedCrossRef
14.
De Vita F, Giuliani F, Silvestris N, Catalano G, Ciardiello F, Orditura M. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev. 2010;36(Suppl 3):S11–5.PubMedCrossRef
15.
Higa GM, Abraham J. Lapatinib in the treatment of breast cancer. Expert Rev Anticancer Ther. 2007;7:1183–92.PubMedCrossRef
16.
Montemurro F, Prat A, Rossi V, Valabrega G, Sperinde J, Peraldo-Neia C, Donadio M, Galvan P, Sapino A, Aglietta M, Baselga J, Scaltriti M. Potential biomarkers of long-term benefit from single-agent trastuzumab or lapatinib in HER2-positive metastatic breast cancer. Mol Oncol. 2014;8:20–6.PubMedCrossRef
17.
Lee JW, Soung YH, Seo SH, Kim SY, Park CH, Wang YP, Park K, Nam SW, Park WS, Kim SH, Lee JY, Yoo NJ, Lee SH. Somatic mutations of erbb2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res. 2006;12:57–61.PubMedCrossRef
18.
Li J, Li G, Wang X, Hibshoosh H, Jin C, Halmos B. Modulation of ERBB2 blockade in ERBB2-positive cancers: the role of ERBB2 mutations and phlda1. PLoS One. 2014;9:e106349.PubMedPubMedCentralCrossRef
19.
Boulbes DR, Arold ST, Chauhan GB, Blachno KV, Deng N, Chang W-C, Jin Q, Huang T-H, Hsu J-M, Brady SW, Bartholomeusz C, Ladbury JE, Stone S, Yu D, Hung M-C, Esteva FJ: HER family kinase domain mutations promote tumor progression and can predict response to treatment in human breast cancer. Molecular oncology 2014
20.
Meng X, Li Y, Tang H, Mao W, Yang H, Wang X, Ding X, Xie S: Drug response to HER2 gatekeeper t798 m mutation in HER2-positive breast cancer. Amino Acids 2015
21.
Trowe T, Boukouvala S, Calkins K, Cutler Jr RE, Fong R, Funke R, Gendreau SB, Kim YD, Miller N, Woolfrey JR, Vysotskaia V, Yang JP, Gerritsen ME, Matthews DJ, Lamb P, Heuer TS. Exel-7647 inhibits mutant forms of ERBB2 associated with lapatinib resistance and neoplastic transformation. Clin Cancer Res. 2008;14:2465–75.
22.
Park YH, Shin HT, Jung HH, Choi YL, Ahn T, Park K, Lee A, Do IG, Kim JY, Ahn JS, Park WY, Im YH. Role of HER2 mutations in refractory metastatic breast cancers: targeted sequencing results in patients with refractory breast cancer. Oncotarget. 2015;6:32027–38.PubMedPubMedCentral
23.
Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, Arribas J. Biosynthesis of tumorigenic HER2 c-terminal fragments by alternative initiation of translation. EMBO J. 2006;25:3234–44.PubMedPubMedCentralCrossRef
24.
Xia W, Liu Z, Zong R, Liu L, Zhao S, Bacus SS, Mao Y, He J, Wulfkuhle JD, Petricoin EF, Osada T, Yang X-Y, Hartman ZC, Clay TM, Blackwell KL, Lyerly HK, Spector NL. Truncated ERBB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ERBB2 kinase inhibitors. Mol Cancer Ther. 2011;10:1367–74.PubMedCrossRef
25.
Xia W, Gooden D, Liu L, Zhao S, Soderblom EJ, Toone EJ, Beyer WF, Walder H, Spector NL. Photo-activated psoralen binds the ERBB2 catalytic kinase domain, blocking ERBB2 signaling and triggering tumor cell apoptosis. PLoS One. 2014;9:e88983.PubMedPubMedCentralCrossRef
26.
Xia W, Petricoin 3rd EF, Zhao S, Liu L, Osada T, Cheng Q, Wulfkuhle JD, Gwin WR, Yang X, Gallagher RI, Bacus S, Lyerly HK, Spector NL. An heregulin-EGFR-HER3 autocrine signaling axis can mediate acquired lapatinib resistance in HER2+ breast cancer models. Breast Cancer Res. 2013;15:R85.PubMedPubMedCentralCrossRef
27.
Xia W, Bacus S, Hegde P, Husain I, Strum J, Liu L, Paulazzo G, Lyass L, Trusk P, Hill J, Harris J, Spector NL. A model of acquired autoresistance to a potent erbb2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci U S A. 2006;103:7795–800.PubMedPubMedCentralCrossRef
28.
Martin AP, Miller A, Emad L, Rahmani M, Walker T, Mitchell C, Hagan MP, Park MA, Yacoub A, Fisher PB, Grant S, Dent P. Lapatinib resistance in hct116 cells is mediated by elevated mcl-1 expression and decreased bak activation and not by ERBB receptor kinase mutation. Mol Pharmacol. 2008;74:807–22.PubMedPubMedCentralCrossRef
29.
Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13:R121.PubMedPubMedCentralCrossRef
30.
Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J. Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mtor/phosphatidylinositol 3-kinase inhibitor nvp-bez235. Cancer Res. 2008;68:9221–30.PubMedPubMedCentralCrossRef
31.
Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos GN, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL. Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res. 2009;15:7266–76.PubMedPubMedCentralCrossRef
32.
Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther. 2006;5:2676–84.PubMedCrossRef
33.
Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PA, Xu R, Bissell MJ. Fam83a confers EGFR-TKI resistance in breast cancer cells and in mice. J Clin Invest. 2012;122:3211–20.PubMedPubMedCentralCrossRef
34.
Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ERBB3) expression and activity attenuates antitumor effect of pI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109:2718–23.PubMedCrossRef
35.
Elster N, Cremona M, Morgan C, Toomey S, Carr A, O'Grady A, Hennessy BT, Eustace AJ. A preclinical evaluation of the pI3K alpha/delta dominant inhibitor bay 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib. Breast Cancer Res Treat. 2015;149:373–83.PubMedCrossRef
36.
Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-dm1 (t-dm1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347–56.PubMedCrossRef
37.
Barok M, Tanner M, Köninki K, Isola J. Trastuzumab-dm1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 2011;306:171–9.PubMedCrossRef
38.
Sahin O, Wang Q, Brady SW, Ellis K, Wang H, Chang C-C, Zhang Q, Priya P, Zhu R, Wong ST, Landis MD, Muller WJ, Esteva FJ, Chang J, Yu D. Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors. Cell Res. 2014;24:542–59.PubMedPubMedCentralCrossRef
39.
Jegg AM, Ward TM, Iorns E, Hoe N, Zhou J, Liu X, Singh S, Landgraf R, Pegram MD. pI3K independent activation of mtorc1 as a target in lapatinib-resistant ERBB2+ breast cancer cells. Breast Cancer Res Treat. 2012;136:683–92.PubMedCrossRef
40.
Vazquez-Martin A, Oliveras-Ferraros C, Colomer R, Brunet J, Menendez JA. Low-scale phosphoproteome analyses identify the mTOR effector p70 s6 kinase 1 as a specific biomarker of the dual-HER1/HER2 tyrosine kinase inhibitor lapatinib (tykerb) in human breast carcinoma cells. Ann Oncol. 2008;19:1097–109.PubMedCrossRef
41.
Gayle SS, Arnold SL, O'Regan RM, Nahta R. Pharmacologic inhibition of mTOR improves lapatinib sensitivity in HER2-overexpressing breast cancer cells with primary trastuzumab resistance. Anti Cancer Agents Med Chem. 2012;12:151–62.CrossRef
42.
Gadgeel SM, Lew DL, Synold TW, LoRusso P, Chung V, Christensen SD, Smith DC, Kingsbury L, Hoering A, Kurzrock R. Phase I study evaluating the combination of lapatinib (a HER2/neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: south west oncology group (SWOG) study s0528. Cancer Chemother Pharmacol. 2013;72:1089–96.PubMedPubMedCentralCrossRef
43.
Garcia-Garcia C, Ibrahim YH, Serra V, Calvo MT, Guzman M, Grueso J, Aura C, Perez J, Jessen K, Liu Y, Rommel C, Tabernero J, Baselga J, Scaltriti M. Dual mTORc1/2 and HER2 blockade results in antitumor activity in preclinical models of breast cancer resistant to anti-HER2 therapy. Clin Cancer Res. 2012;18:2603–12.PubMedCrossRef
44.
Spector NL, Xia W, Burris 3rd H, Hurwitz H, Dees EC, Dowlati A, O'Neil B, Overmoyer B, Marcom PK, Blackwell KL, Smith DA, Koch KM, Stead A, Mangum S, Ellis MJ, Liu L, Man AK, Bremer TM, Harris J, Bacus S. Study of the biologic effects of lapatinib, a reversible inhibitor of ERBB1 and ERBB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol. 2005;23:2502–12.PubMedCrossRef
45.
O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/Akt signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010;9:1489–502.PubMedCrossRef
46.
Brady SW, Zhang J, Tsai M-H, Yu D: Pi3k-independent mTOR activation promotes lapatinib resistance and iap expression that can be effectively reversed by mTOR and hsp90 inhibition. Cancer Biology & Therapy 2015:0.
47.
48.
Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the pi3k pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395–402.PubMedCrossRef
49.
Kataoka Y, Mukohara T, Shimada H, Saijo N, Hirai M, Minami H. Association between gain-of-function mutations in pik3ca and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol. 2010;21:255–62.PubMedCrossRef
50.
Wang L, Zhang Q, Zhang J, Sun S, Guo H, Jia Z, Wang B, Shao Z, Wang Z, Hu X. Pi3k pathway activation results in low efficacy of both trastuzumab and lapatinib. BMC Cancer. 2011;11:248.PubMedPubMedCentralCrossRef
51.
Brady SW, Zhang J, Seok D, Wang H, Yu D. Enhanced pi3k p110α signaling confers acquired lapatinib resistance that can be effectively reversed by a p110α-selective pi3k inhibitor. Mol Cancer Ther. 2014;13:60–70.PubMedCrossRef
52.
Ranzani M, Annunziato S, Calabria A, Brasca S, Benedicenti F, Gallina P, Naldini L, Montini E. Lentiviral vector-based insertional mutagenesis identifies genes involved in the resistance to targeted anticancer therapies. Mol Ther. 2014;22:2056–68.PubMedPubMedCentralCrossRef
53.
Krop I, Winer EP. Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer. Clin Cancer Res. 2014;20:15–20.PubMedCrossRef
54.
Hanker AB, Pfefferle AD, Balko JM, Kuba MG, Young CD, Sánchez V, Sutton CR, Cheng H, Perou CM, Zhao JJ, Cook RS, Arteaga CL. Mutant pik3ca accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci USA. 2013;110:14372–7.PubMedPubMedCentralCrossRef
55.
Brady SW, Zhang J, Seok D, Wang H, Yu D. Enhanced pi3k p110alpha signaling confers acquired lapatinib resistance that can be effectively reversed by a p110alpha-selective pi3k inhibitor. Mol Cancer Ther. 2014;13:60–70.PubMedCrossRef
56.
Kadota M, Sato M, Duncan B, Ooshima A, Yang HH, Diaz-Meyer N, Gere S, Kageyama S-I, Fukuoka J, Nagata T, Tsukada K, Dunn BK, Wakefield LM, Lee MP. Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of pik3ca. Cancer Res. 2009;69:7357–65.PubMedPubMedCentralCrossRef
57.
Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. Pik3ca gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene. 2005;24:1477–80.PubMedCrossRef
58.
59.
Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61–70.
60.
Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J, Rimawi M, Schiff R, Arteaga C, Osborne CK, Chang JC. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 2011;29:166–73.PubMedCrossRef
61.
Xu B, Guan Z, Shen Z, Tong Z, Jiang Z, Yang J, DeSilvio M, Russo M, Leigh M, Ellis C. Association of phosphatase and tensin homolog low and phosphatidylinositol 3-kinase catalytic subunit alpha gene mutations on outcome in human epidermal growth factor receptor 2-positive metastatic breast cancer patients treated with first-line lapatinib plus paclitaxel or paclitaxel alone. Breast Cancer Res. 2014;16:405.PubMedPubMedCentralCrossRef
62.
Depowski PL, Rosenthal SI, Ross JS. Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer. Mod Pathol. 2001;14:672–6.PubMedCrossRef
63.
Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R. Pik3ca mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.PubMedCrossRef
64.
Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS. Breast cancer-associated pik3ca mutations are oncogenic in mammary epithelial cells. Cancer Res. 2005;65:10992–1000.PubMedCrossRef
65.
Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL. Combining lapatinib (gw572016), a small molecule inhibitor of ERBB1 and ERBB2 tyrosine kinases, with therapeutic anti-ERBB2 antibodies enhances apoptosis of ERBB2-overexpressing breast cancer cells. Oncogene. 2005;24:6213–21.PubMedCrossRef
66.
Johnston S, Trudeau M, Kaufman B, Boussen H, Blackwell K, LoRusso P, Lombardi DP, Ben Ahmed S, Citrin DL, DeSilvio ML, Harris J, Westlund RE, Salazar V, Zaks TZ, Spector NL. Phase ii study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy. J Clin Oncol. 2008;26:1066–72.PubMedCrossRef
67.
Xia W, Husain I, Liu L, Bacus S, Saini S, Spohn J, Pry K, Westlund R, Stein SH, Spector NL. Lapatinib antitumor activity is not dependent upon phosphatase and tensin homologue deleted on chromosome 10 in ERBB2-overexpressing breast cancers. Cancer Res. 2007;67:1170–5.PubMedCrossRef
68.
Dave B, Migliaccio I, Gutierrez MC, Wu MF, Chamness GC, Wong H, Narasanna A, Chakrabarty A, Hilsenbeck SG, Huang J, Rimawi M, Schiff R, Arteaga C, Osborne CK, Chang JC. Loss of phosphatase and tensin homolog or phosphoinositol-3 kinase activation and response to trastuzumab or lapatinib in human epidermal growth factor receptor 2-overexpressing locally advanced breast cancers. J Clin Oncol. 2010;29:166–73.PubMedPubMedCentralCrossRef
69.
Zhang Z, Wang J, Ji D, Wang C, Liu R, Wu Z, Liu L, Zhu D, Chang J, Geng R, Xiong L, Fang Q, Li J. Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of lapatinib unresponsiveness in her2-positive gastric cancer. Clin Cancer Res. 2014;20:4559–73.PubMedCrossRef
70.
Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6:117–27.PubMedCrossRef
71.
Nuciforo PG, Aura C, Holmes E, Prudkin L, Jimenez J, Martinez P, Ameels H, de la Pena L, Ellis C, Eidtmann H, Piccart-Gebhart MJ, Scaltriti M, Baselga J: Benefit to neoadjuvant anti-human epidermal growth factor receptor 2 (HER2)-targeted therapies in HER2-positive primary breast cancer is independent of phosphatase and tensin homolog deleted from chromosome 10 (PTEN) status. Ann Oncol 2015
72.
Zoppoli G, Moran E, Soncini D, Cea M, Garuti A, Rocco I, Cirmena G, Grillo V, Bagnasco L, Icardi G, Ansaldi F, Parodi S, Patrone F, Ballestrero A, Nencioni A. Ras-induced resistance to lapatinib is overcome by MEK inhibition. Curr Cancer Drug Targets. 2010;10:168–75.PubMedCrossRef
73.
74.
Roberts PJ, Usary JE, Darr DB, Dillon PM, Pfefferle AD, Whittle MC, Duncan JS, Johnson SM, Combest AJ, Jin J, Zamboni WC, Johnson GL, Perou CM, Sharpless NE. Combined pi3k/mTOR and MEK inhibition provides broad antitumor activity in faithful murine cancer models. Clin Cancer Res. 2012;18:5290–303.PubMedPubMedCentralCrossRef
75.
Wang Z, Ahmad A, Li Y, Banerjee S, Kong D, Sarkar FH. Forkhead box m1 transcription factor: a novel target for cancer therapy. Cancer Treat Rev. 2010;36:151–6.PubMedCrossRef
76.
77.
Francis RE, Myatt SS, Krol J, Hartman J, Peck B, McGovern UB, Wang J, Guest SK, Filipovic A, Gojis O, Palmieri C, Peston D, Shousha S, Yu Q, Sicinski P, Coombes RC, Lam EW. Foxm1 is a downstream target and marker of HER2 overexpression in breast cancer. Int J Oncol. 2009;35:57–68.PubMedPubMedCentral
78.
Matkar S, Sharma P, Gao S, Gurung B, Katona BW, Liao J, Muhammad AB, Kong X-C, Wang L, Jin G, Dang CV, Hua X. An epigenetic pathway regulates sensitivity of breast cancer cells to HER2 inhibition via foxo/c-myc axis. Cancer Cell. 2015;28:472–85.PubMedPubMedCentralCrossRef
79.
McDermott MSJ, Browne BC, Conlon NT, O’Brien NA, Slamon DJ, Henry M, Meleady P, Clynes M, Dowling P, Crown J, O’Donovan N. Pp2a inhibition overcomes acquired resistance to her2 targeted therapy. Mol Cancer. 2014;13:157.PubMedPubMedCentralCrossRef
80.
Hizli AA, Chi Y, Swanger J, Carter JH, Liao Y, Welcker M, Ryazanov AG, Clurman BE. Phosphorylation of eukaryotic elongation factor 2 (EEF2) by cyclin a-cyclin-dependent kinase 2 regulates its inhibition by EEF2 kinase. Mol Cell Biol. 2013;33:596–604.PubMedPubMedCentralCrossRef
81.
Wong LL, Chang CF, Koay ES, Zhang D. Tyrosine phosphorylation of pp2a is regulated by HER-2 signalling and correlates with breast cancer progression. Int J Oncol. 2009;34:1291–301.PubMed
82.
Saddoughi SA, Gencer S, Peterson YK, Ward KE, Mukhopadhyay A, Oaks J, Bielawski J, Szulc ZM, Thomas RJ, Selvam SP, Senkal CE, Garrett-Mayer E, De Palma RM, Fedarovich D, Liu A, Habib AA, Stahelin RV, Perrotti D, Ogretmen B. Sphingosine analogue drug fty720 targets i2pp2a/set and mediates lung tumour suppression via activation of pp2a-ripk1-dependent necroptosis. EMBO Mol Med. 2013;5:105–21.PubMedCrossRef
83.
Bialojan C, Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics Biochem J. 1988;256:283–90.PubMed
84.
Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM. Escape from her-family tyrosine kinase inhibitor therapy by the kinase-inactive her3. Nature. 2007;445:437–41.PubMedPubMedCentralCrossRef
85.
Kalous O, Conklin D, Desai AJ, O'Brien NA, Ginther C, Anderson L, Cohen DJ, Britten CD, Taylor I, Christensen JG, Slamon DJ, Finn RS. Dacomitinib (pf-00299804), an irreversible pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib. Mol Cancer Ther. 2012;11:1978–87.PubMedCrossRef
86.
Falchook GS, Moulder S, Naing A, Wheler JJ, Hong DS, Piha-Paul SA, Tsimberidou AM, Fu S, Zinner R, Janku F, Jiang Y, Huang M, Parkhurst KL, Kurzrock R. A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer. Investig New Drugs. 2015;33:177–86.CrossRef
87.
Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor zd1839 (iressa) inhibits HER2/neu (ERBB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res. 2001;61:8887–95.PubMed
88.
Normanno N, Campiglio M, De LA, Somenzi G, Maiello M, Ciardiello F, Gianni L, Salomon DS, Menard S. Cooperative inhibitory effect of zd1839 (iressa) in combination with trastuzumab (herceptin) on human breast cancer cell growth. Ann Oncol. 2002;13:65–72.PubMedCrossRef
89.
Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:5878–87.PubMedCrossRef
90.
Nam HJ, Ching KA, Kan J, Kim HP, Han SW, Im SA, Kim TY, Christensen JG, Oh DY, Bang YJ. Evaluation of the antitumor effects and mechanisms of pf00299804, a pan-HER inhibitor, alone or in combination with chemotherapy or targeted agents in gastric cancer. Mol Cancer Ther. 2011;11:439–51.PubMedCrossRef
91.
Zhang D, Pal A, Bornmann WG, Yamasaki F, Esteva FJ, Hortobagyi GN, Bartholomeusz C, Ueno NT. Activity of lapatinib is independent of EGFR expression level in HER2-overexpressing breast cancer cells. Mol Cancer Ther. 2008;7:1846–50.PubMedPubMedCentralCrossRef
92.
Chen CT, Kim H, Liska D, Gao S, Christensen JG, Weiser MR. Met activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol Cancer Ther. 2012;11:660–9.PubMedPubMedCentralCrossRef
93.
Amin DN, Sergina N, Ahuja D, McMahon M, Blair JA, Wang D, Hann B, Koch KM, Shokat KM, Moasser MM. Resiliency and vulnerability in the HER2-HER3 tumorigenic driver. Sci Transl Med. 2010;2:16ra17.CrossRef
94.
Myatt SS, Lam EW. The emerging roles of forkhead box (fox) proteins in cancer. Nat Rev Cancer. 2007;7:847–59.PubMedCrossRef
95.
Garrett JT, Sutton CR, Kuba MG, Cook RS, Arteaga CL. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clinical cancer research : an official journal of the American Association for Cancer Research. 2013;19:610–9.CrossRef
96.
Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, Dave B, Cook RS, Pao W, McKinely E, Manning HC, Chang J, Arteaga CL. Transcriptional and posttranslational up-regulation of HER3 (ERBB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A. 2011;108:5021–6.PubMedPubMedCentralCrossRef
97.
Awasthi S, Hamburger AW. Heregulin negatively regulates transcription of ERBB2/3 receptors via an Akt-mediated pathway. J Cell Physiol. 2014;229:1831–41.PubMedPubMedCentralCrossRef
98.
Huang W, QD W, Zhang M, YL K, PR C, Zheng W, JH X, M Y. Novel HSP90 inhibitor fw-04-806 displays potent antitumor effects in HER2-positive breast cancer cells as a single agent or in combination with lapatinib. Cancer Lett. 2015;356:862–71.PubMedCrossRef
99.
Kim HP, Han SW, Song SH, Jeong EG, Lee MY, Hwang D, Im SA, Bang YJ, Kim TY. Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene. 2014;33:3334–41.PubMedCrossRef
100.
Leung W-Y, Roxanis I, Sheldon H, Buffa FM, Li J-L, Harris AL, Kong A: Combining lapatinib and pertuzumab to overcome lapatinib resistance due to nrg1-mediated signalling in HER2-amplified breast cancer. Oncotarget 2015
101.
Lyu H, Yang XH, Edgerton SM, Thor AD, Wu X, He Z, Liu B. The ERBB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells. Oncotarget. 2016;7:2921–35.PubMed
102.
Wu Y, Zhang Y, Wang M, Li Q, Qu Z, Shi V, Kraft P, Kim S, Gao Y, Pak J, Youngster S, Horak ID, Greenberger LM. Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models. Mol Cancer Ther. 2013;12:427–37.PubMedCrossRef
103.
Kang JC, Poovassery JS, Bansal P, You S, Manjarres IM, Ober RJ, Ward ES. Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. mAbs. 2014;6:340–53.PubMedCrossRef
104.
McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, Zhang B, Luus L, Overland R, Nguyen S, Gu J, Kohli N, Wallace M, Feldhaus MJ, Kudla AJ, Schoeberl B, Nielsen UB. Antitumor activity of a novel bispecific antibody that targets the ERBB2/ERBB3 oncogenic unit and inhibits heregulin-induced activation of ERBB3. Mol Cancer Ther. 2012;11:582–93.PubMedCrossRef
105.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J, Ribas A, Li J, Moffat J, Sutherlin DP, Koeppen H, Merchant M, Neve R, Settleman J. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature. 2012;487:505–9.PubMedPubMedCentralCrossRef
106.
Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinib-mediated growth inhibition of HER2-amplified cancer cells. Cancer Sci. 2013;104:1618–25.PubMedCrossRef
107.
Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL. Anti-tumor activity of gw572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/ERBB2 and downstream ERK1/2 and Akt pathways. Oncogene. 2002;21:6255–63.PubMedCrossRef
108.
Xia W, Liu LH, Ho P, Spector NL. Truncated ERBB2 receptor (p95erbb2) is regulated by heregulin through heterodimer formation with ERBB3 yet remains sensitive to the dual EGFR/ERBB2 kinase inhibitor gw572016. Oncogene. 2004;23:646–53.PubMedCrossRef
109.
Canfield K, Li J, Wilkins OM, Morrison MM, Ung M, Wells W, Williams CR, Liby KT, Vullhorst D, Buonanno A, Hu H, Schiff R, Cook RS, Kurokawa M: Receptor tyrosine kinase ERBB4 mediates acquired resistance to ERBB2 inhibitors in breast cancer cells. Cell cycle (Georgetown, Tex) 2015:0.
110.
Stuhlmiller TJ, Miller SM, Zawistowski JS, Nakamura K, Beltran AS, Duncan JS, Angus SP, Collins KA, Granger DA, Reuther RA, Graves LM, Gomez SM, Kuan PF, Parker JS, Chen X, Sciaky N, Carey LA, Earp HS, Jin J, Johnson GL. Inhibition of lapatinib-induced kinome reprogramming in ERBB2-positive breast cancer by targeting bet family bromodomains. Cell Rep. 2015;11:390–404.PubMedPubMedCentralCrossRef
111.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65:11118–28.PubMedCrossRef
112.
Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13:2795–803.PubMedCrossRef
113.
Saxena NK, Taliaferro-Smith L, Knight BB, Merlin D, Anania FA, O'Regan RM, Sharma D. Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Res. 2008;68:9712–22.PubMedPubMedCentralCrossRef
114.
Nahta R, Yuan LX, Du Y, Esteva FJ. Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling. Mol Cancer Ther. 2007;6:667–74.PubMedCrossRef
115.
Azuma K, Tsurutani J, Sakai K, Kaneda H, Fujisaka Y, Takeda M, Watatani M, Arao T, Satoh T, Okamoto I, Kurata T, Nishio K, Nakagawa K. Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure. Biochem Biophys Res Commun. 2011;407:219–24.PubMedCrossRef
116.
Lee YY, Kim H-P, Kang MJ, Cho B-K, Han S-W, Kim T-Y, Yi EC. Phosphoproteomic analysis identifies activated met-axis pi3k/Akt and MAPK/ERK in lapatinib-resistant cancer cell line. Exp Mol Med. 2013;45:e64.PubMedPubMedCentralCrossRef
117.
Rexer BN, Ham AJL, Rinehart C, Hill S, de Matos G-IN, González-Angulo AM, Mills GB, Dave B, Chang JC, Liebler DC, Arteaga CL. Phosphoproteomic mass spectrometry profiling links SRC family kinases to escape from HER2 tyrosine kinase inhibition. Oncogene. 2011;30:4163–74.PubMedPubMedCentralCrossRef
118.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, Janne PA. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.PubMedCrossRef
119.
Yano S, Wang W, Li Q, Matsumoto K, Sakurama H, Nakamura T, Ogino H, Kakiuchi S, Hanibuchi M, Nishioka Y, Uehara H, Mitsudomi T, Yatabe Y, Sone S. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res. 2008;68:9479–87.PubMedCrossRef
120.
121.
Xu H, Stabile LP, Gubish CT, Gooding WE, Grandis JR, Siegfried JM. Dual blockade of EGFR and c-MET abrogates redundant signaling and proliferation in head and neck carcinoma cells. Clin Cancer Res. 2011;17:4425–38.PubMedPubMedCentralCrossRef
122.
Stabile LP, Rothstein ME, Keohavong P, Lenzner D, Land SR, Gaither-Davis AL, Kim KJ, Kaminski N, Siegfried JM. Targeting of both the c-MET and EGFR pathways results in additive inhibition of lung tumorigenesis in transgenic mice. Cancers (Basel). 2010;2:2153–70.CrossRef
123.
Wang Q, Quan H, Zhao J, Xie C, Wang L, Lou L. Ron confers lapatinib resistance in HER2-positive breast cancer cells. Cancer Lett. 2013;340:43–50.PubMedCrossRef
124.
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin AM, Gilmer TM. Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of axl. Cancer Res. 2009;69:6871–8.PubMedCrossRef
125.
Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang S-Y, Robell K, Kahana JA, Geske RS, Kleymenova EV, Choudhry AE, Lai Z, Leber JD, Minthorn EA, Strum SL, Wood ER, Huang PS, Copeland RA, Kumar R. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008;68:2366–74.PubMedCrossRef
126.
Chen FL, Xia W, Spector NL. Acquired resistance to small molecule erbb2 tyrosine kinase inhibitors. Clin Cancer Res. 2008;14:6730–4.PubMedCrossRef
127.
De Luca A, D'Alessio A, Gallo M, Maiello MR, Bode AM, Normanno N. Src and cxcr4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib. Cell Cycle. 2014;13:148–56.PubMedCrossRef
128.
Hong YS, Kim J, Pectasides E, Fox C, Hong SW, Ma Q, Wong GS, Peng S, Stachler MD, Thorner AR, Van Hummelen P, Bass AJ. Src mutation induces acquired lapatinib resistance in ERBB2-amplified human gastroesophageal adenocarcinoma models. PLoS One. 2014;9:e109440.PubMedPubMedCentralCrossRef
129.
Nam HJ, Im SA, Oh DY, Elvin P, Kim HP, Yoon YK, Min A, Song SH, Han SW, Kim TY, Bang YJ. Antitumor activity of saracatinib (azd0530), a c-src/abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer. Mol Cancer Ther. 2013;12:16–26.PubMedCrossRef
130.
Formisano L, Nappi L, Rosa R, Marciano R, D'Amato C, D'Amato V, Damiano V, Raimondo L, Iommelli F, Scorziello A, Troncone G, Veneziani B, Parsons SJ, De Placido S, Bianco R. Epidermal growth factor-receptor activation modulates src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res. 2014;16:R45.PubMedPubMedCentralCrossRef
131.
Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang Y-c, Shou J, Bissell MJ, CK O, Schiff R. Β1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Res. 2011;13:R84.PubMedPubMedCentralCrossRef
132.
Xiang B, Chatti K, Qiu H, Lakshmi B, Krasnitz A, Hicks J, Yu M, Miller WT, Muthuswamy SK. Brk is coamplified with erbb2 to promote proliferation in breast cancer. Proc Natl Acad Sci U S A. 2008;105:12463–8.PubMedPubMedCentralCrossRef
133.
Chen S, Li X, Feng J, Chang Y, Wang Z, Wen A. Autophagy facilitates the lapatinib resistance of HER2 positive breast cancer cells. Med Hypotheses. 2011;77:206–8.PubMedCrossRef
134.
Zou Z, Yuan Z, Zhang Q, Long Z, Chen J, Tang Z, Zhu Y, Chen S, Xu J, Yan M, Wang J, Liu Q. Aurora kinase a inhibition-induced autophagy triggers drug resistance in breast cancer cells. Autophagy. 2012;8:1798–810.PubMedPubMedCentralCrossRef
135.
Chen YJ, Chi CW, Su WC, Huang HL. Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma. Oncotarget. 2014;5:4845–54.PubMedPubMedCentralCrossRef
136.
Negri T, Tarantino E, Orsenigo M, Reid JF, Gariboldi M, Zambetti M, Pierotti MA, Pilotti S. Chromosome band 17q21 in breast cancer: significant association between beclin 1 loss and her2/neu amplification. Genes, chromosomes & cancer. 2010;49:901–9.CrossRef
137.
138.
Cufí S, Vazquez-Martin A, Oliveras-Ferraros C, Corominas-Faja B, Urruticoechea A, Martin-Castillo B, Menendez JA. Autophagy-related gene 12 (atg12) is a novel determinant of primary resistance to her2-targeted therapies: utility of transcriptome analysis of the autophagy interactome to guide breast cancer treatment. Oncotarget. 2012;3:1600–14.PubMedPubMedCentralCrossRef
139.
Chen S, Zhu X, Qiao H, Ye M, Lai X, Yu S, Ding L, Wen A, Zhang J. Protective autophagy promotes the resistance of HER2-positive breast cancer cells to lapatinib. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 2016;37:2321–31.CrossRef
140.
Martin AP, Mitchell C, Rahmani M, Nephew KP, Grant S, Dent P. Inhibition of mcl-1 enhances lapatinib toxicity and overcomes lapatinib resistance via bak-dependent autophagy. Cancer Biol Ther. 2009;8:2084–96.PubMedPubMedCentralCrossRef
141.
Wertheim GBW, Yang TW, Pan T-c, Ramne A, Liu Z, Gardner HP, Dugan KD, Kristel P, Kreike B, van de Vijver MJ, Cardiff RD, Reynolds C, Chodosh LA. The SNF1-related kinase, hunk, is essential for mammary tumor metastasis. Proc Natl Acad Sci U S A. 2009;106:15855–60.PubMedPubMedCentralCrossRef
142.
Quintela-Fandino M, Arpaia E, Brenner D, Goh T, Yeung FA, Blaser H, Alexandrova R, Lind EF, Tusche MW, Wakeham A, Ohashi PS, Mak TW. Hunk suppresses metastasis of basal type breast cancers by disrupting the interaction between pp2a and cofilin-1. Proc Natl Acad Sci U S A. 2010;107:2622–7.PubMedPubMedCentralCrossRef
143.
Yeh ES, Yang TW, Jung JJ, Gardner HP, Cardiff RD, Chodosh LA. Hunk is required for HER2/neu-induced mammary tumorigenesis. J Clin Invest. 2011;121:866–79.PubMedPubMedCentralCrossRef
144.
Yeh ES, Belka GK, Vernon AE, Chen C-C, Jung JJ, Chodosh LA. Hunk negatively regulates c-myc to promote Akt-mediated cell survival and mammary tumorigenesis induced by loss of pten. Proc Natl Acad Sci U S A. 2013;110:6103–8.PubMedPubMedCentralCrossRef
145.
Yeh ES, Abt MA, Hill EG. Regulation of cell survival by hunk mediates breast cancer resistance to HER2 inhibitors. Breast Cancer Res Treat. 2015;149:91–8.PubMedCrossRef
146.
Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, Kondo S, Dumont DJ, Gutterman JU, Walker CL, Slingerland JM, Mills GB. The energy sensing lkb1-ampk pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol. 2007;9:218–24.PubMedCrossRef
147.
Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27kip1 promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002;277:28706–13.PubMedCrossRef
148.
Fujita N, Sato S, Tsuruo T. Phosphorylation of p27kip1 at threonine 198 by p90 ribosomal protein s6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2003;278:49254–60.PubMedCrossRef
149.
Foster FM, Owens TW, Tanianis-Hughes J, Clarke RB, Brennan K, Bundred NJ, Streuli CH. Targeting inhibitor of apoptosis proteins in combination with ERBB antagonists in breast cancer. Breast Cancer Res. 2009;11:R41.PubMedPubMedCentralCrossRef
150.
Aird KM, Ghanayem RB, Peplinski S, Lyerly HK, Devi GR. X-linked inhibitor of apoptosis protein inhibits apoptosis in inflammatory breast cancer cells with acquired resistance to an ERBB1/2 tyrosine kinase inhibitor. Mol Cancer Ther. 2010;9:1432–42.PubMedPubMedCentralCrossRef
151.
Yamagiwa Y, Marienfeld C, Meng F, Holcik M, Patel T. Translational regulation of x-linked inhibitor of apoptosis protein by interleukin-6: a novel mechanism of tumor cell survival. Cancer Res. 2004;64:1293–8.PubMedCrossRef
152.
Asanuma H, Torigoe T, Kamiguchi K, Hirohashi Y, Ohmura T, Hirata K, Sato M, Sato N. Survivin expression is regulated by coexpression of human epidermal growth factor receptor 2 and epidermal growth factor receptor via phosphatidylinositol 3-kinase/Akt signaling pathway in breast cancer cells. Cancer Res. 2005;65:11018–25.PubMedCrossRef
153.
Williams KP, Allensworth JL, Ingram SM, Smith GR, Aldrich AJ, Sexton JZ, Devi GR. Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization. Cancer Lett. 2013;337:77–89.PubMedPubMedCentralCrossRef
154.
Morse MA, Wei J, Hartman Z, Xia W, Ren X-R, Lei G, Barry WT, Osada T, Hobeika AC, Peplinski S, Jiang H, Devi GR, Chen W, Spector N, Amalfitano A, Lyerly HK, Clay TM. Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo. International journal of cancer Journal international du cancer. 2010;126:2893–903.PubMedPubMedCentral
155.
Tanizaki J, Okamoto I, Fumita S, Okamoto W, Nishio K, Nakagawa K. Roles of BIM induction and survivin downregulation in lapatinib-induced apoptosis in breast cancer cells with HER2 amplification. Oncogene. 2011;30:4097–106.PubMedCrossRef
156.
Valabrega G, Capellero S, Cavalloni G, Zaccarello G, Petrelli A, Migliardi G, Milani A, Peraldo-Neia C, Gammaitoni L, Sapino A, Pecchioni C, Moggio A, Giordano S, Aglietta M, Montemurro F. HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Res Treat. 2011;130:29–40.PubMedCrossRef
157.
Mitchell C, Yacoub A, Hossein H, Martin AP, Bareford MD, Eulitt P, Yang C, Nephew KP, Dent P. Inhibition of mcl-1 in breast cancer cells promotes cell death in vitro and in vivo. Cancer Biol Ther. 2010;10:903–17.PubMedPubMedCentralCrossRef
158.
Cruickshanks N, Hamed HA, Booth L, Tavallai S, Syed J, Sajithlal GB, Grant S, Poklepovic A, Dent P. Histone deacetylase inhibitors restore toxic bh3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy. Cancer Biology & Therapy. 2013;14:982–96.CrossRef
159.
Moody SE, Schinzel AC, Singh S, Izzo F, Strickland MR, Luo L, Thomas SR, Boehm JS, Kim SY, Wang ZC, Hahn WC: Prkaca mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling. Oncogene 2014;0
160.
Christenson JL, Denny EC, Kane SE. T-darpp overexpression in HER2-positive breast cancer confers a survival advantage in lapatinib. Oncotarget. 2015;6:33134–45.PubMedPubMedCentral
161.
Lee J, Bartholomeusz C, Mansour O, Humphries J, Hortobagyi GN, Ordentlich P, Ueno NT. A class I histone deacetylase inhibitor, entinostat, enhances lapatinib efficacy in HER2-overexpressing breast cancer cells through foxo3-mediated bim1 expression. Breast Cancer Res Treat. 2014;146:259–72.PubMedPubMedCentralCrossRef
162.
Farrugia MK, Sharma SB, Lin C-C, McLaughlin SL, Vanderbilt DB, Ammer AG, Salkeni MA, Stoilov P, Agazie YM, Creighton CJ, Ruppert JM. Regulation of anti-apoptotic signaling by kruppel-like factors 4 and 5 mediates lapatinib resistance in breast cancer. Cell Death Dis. 2015;6:e1699.PubMedPubMedCentralCrossRef
163.
Corcoran C, Friel AM, Duffy MJ, Crown J, O'Driscoll L. Intracellular and extracellular micrornas in breast cancer. Clin Chem. 2011;57:18–32.PubMedCrossRef
164.
Zhang B, Pan X, Cobb GP, Anderson TA. Micrornas as oncogenes and tumor suppressors. Dev Biol. 2007;302:1–12.PubMedCrossRef
165.
Iorio MV, Ferracin M, Liu C-G, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM. Microrna gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065–70.PubMedCrossRef
166.
Iorio MV, Casalini P, Piovan C, Di Leva G, Merlo A, Triulzi T, Menard S, Croce CM, Tagliabue E. Microrna-205 regulates her3 in human breast cancer. Cancer Res. 2009;69:2195–200.PubMedCrossRef
167.
De Cola A, Volpe S, Budani MC, Ferracin M, Lattanzio R, Turdo A, D'Agostino D, Capone E, Stassi G, Todaro M, Di Ilio C, Sala G, Piantelli M, Negrini M, Veronese A, De Laurenzi V. Mir-205-5p-mediated downregulation of ERBB/HER receptors in breast cancer stem cells results in targeted therapy resistance. Cell Death Dis. 2015;6:e1823.PubMedPubMedCentralCrossRef
168.
Corcoran C, Rani S, Breslin S, Gogarty M, Ghobrial IM, Crown J, O’Driscoll L. Mir-630 targets IGF1r to regulate response to her-targeting drugs and overall cancer cell progression in HER2 over-expressing breast cancer. Mol Cancer. 2014;13:71.PubMedPubMedCentralCrossRef
169.
Corcoran C, Rani S, O'Brien K, O'Neill A, Prencipe M, Sheikh R, Webb G, McDermott R, Watson W, Crown J, O'Driscoll L. Docetaxel-resistance in prostate cancer: evaluating associated phenotypic changes and potential for resistance transfer via exosomes. PLoS One. 2012;7:e50999.PubMedPubMedCentralCrossRef
170.
Shah AN, Summy JM, Zhang J, Park SI, Parikh NU, Gallick GE. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol. 2007;14:3629–37.PubMedCrossRef
171.
Cheng GZ, Chan J, Wang Q, Zhang W, Sun CD, Wang LH. Twist transcriptionally up-regulates akt2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 2007;67:1979–87.PubMedCrossRef
172.
Yang AD, Fan F, Camp ER, van Buren G, Liu W, Somcio R, Gray MJ, Cheng H, Hoff PM, Ellis LM. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12:4147–53.PubMedCrossRef
173.
Zhang A-X, Lu F-Q, Yang Y-P, Ren X-Y, Li Z-F, Zhang W: Microrna-217 overexpression induces drug resistance and invasion of breast cancer cells by targeting pten signaling. Cell biology international 2015
174.
Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA MIR-125a or MIR-125b. J Biol Chem. 2007;282:1479–86.PubMedCrossRef
175.
Park SY, Lee HE, Li H, Shipitsin M, Gelman R, Polyak K. Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 2010;16:876–87.PubMedPubMedCentralCrossRef
176.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983–8.PubMedPubMedCentralCrossRef
177.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, Hilsenbeck SG, Pavlick A, Zhang X, Chamness GC, Wong H, Rosen J, Chang JC. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. JNCI Journal of the National Cancer Institute. 2008;100:672–9.PubMedCrossRef
178.
Lesniak D, Sabri S, Xu Y, Graham K, Bhatnagar P, Suresh M, Abdulkarim B. Spontaneous epithelial-mesenchymal transition and resistance to HER-2-targeted therapies in HER-2-positive luminal breast cancer. PLoS One. 2013;8:e71987.PubMedPubMedCentralCrossRef
179.
Lower EE, Glass E, Blau R, Harman S. HER-2/neu expression in primary and metastatic breast cancer. Breast Cancer Res Treat. 2009;113:301–6.PubMedCrossRef
180.
Honeth G, Bendahl PO, Ringner M, Saal LH, Gruvberger-Saal SK, Lovgren K, Grabau D, Ferno M, Borg A, Hegardt C. The cd44+/cd24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.PubMedPubMedCentralCrossRef
181.
Kristiansen G, Winzer KJ, Mayordomo E, Bellach J, Schluns K, Denkert C, Dahl E, Pilarsky C, Altevogt P, Guski H, Dietel M. Cd24 expression is a new prognostic marker in breast cancer. Clin Cancer Res. 2003;9:4906–13.PubMed
182.
Hosonaga M, Arima Y, Sugihara E, Kohno N, Saya H. Expression of cd24 is associated with HER2 expression and supports HER2-akt signaling in HER2-positive breast cancer cells. Cancer Sci. 2014;105:779–87.PubMedPubMedCentralCrossRef
183.
Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120–30.PubMedPubMedCentralCrossRef
184.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, Jacquemier J, Viens P, Kleer CG, Liu S, Schott A, Hayes D, Birnbaum D, Wicha MS, Dontu G. Aldh1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67.PubMedPubMedCentralCrossRef
185.
Cicalese A, Bonizzi G, Pasi CE, Faretta M, Ronzoni S, Giulini B, Brisken C, Minucci S, Di Fiore PP, Pelicci PG. The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell. 2009;138:1083–95.PubMedCrossRef
186.
Singh JK, Farnie G, Bundred NJ, Simoes BM, Shergill A, Landberg G, Howell SJ, Clarke RB. Targeting cxcr1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin Cancer Res. 2012;19:643–56.PubMedPubMedCentralCrossRef
187.
Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42.PubMedCrossRef
188.
Wend P, Holland JD, Ziebold U, Birchmeier W. Wnt signaling in stem and cancer stem cells. Semin Cell Dev Biol. 2010;21:855–63.PubMedCrossRef
189.
Huang S-MA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S, Hild M, Shi X, Wilson CJ, Mickanin C, Myer V, Fazal A, Tomlinson R, Serluca F, Shao W, Cheng H, Shultz M, Rau C, Schirle M, Schlegl J, Ghidelli S, Fawell S, Lu C, Curtis D, Kirschner MW, Lengauer C, Finan PM, Tallarico JA, Bouwmeester T, Porter JA, Bauer A, Cong F. Tankyrase inhibition stabilizes axin and antagonizes WNT signalling. Nature. 2009;461:614–20.PubMedCrossRef
190.
Creedon H, Gómez-Cuadrado L, Tarnauskaitė Ž, Balla J, Canel M, MacLeod KG, Serrels B, Fraser C, Unciti-Broceta A, Tracey N, Le Bihan T, Klinowska T, Sims AH, Byron A, Brunton VG: Identification of novel pathways linking epithelial-to-mesenchymal transition with resistance to HER2-targeted therapy. Oncotarget 2016
191.
Liu J, Chen X, Ward T, Mao Y, Bockhorn J, Liu X, Wang G, Pegram M, Shen K. Niclosamide inhibits epithelial-mesenchymal transition and tumor growth in lapatinib-resistant human epidermal growth factor receptor 2-positive breast cancer. Int J Biochem Cell Biol. 2016;71:12–23.PubMedCrossRef
192.
Spector NL, Yarden Y, Smith B, Lyass L, Trusk P, Pry K, Hill JE, Xia W, Seger R, Bacus SS. Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells. Proc Natl Acad Sci U S A. 2007;104:10607–12.PubMedPubMedCentralCrossRef
193.
Lin SC, Chien CW, Lee JC, Yeh YC, Hsu KF, Lai YY, Tsai SJ. Suppression of dual-specificity phosphatase-2 by hypoxia increases chemoresistance and malignancy in human cancer cells. J Clin Invest. 2011;121:1905–16.PubMedPubMedCentralCrossRef
194.
Karakashev SV, Reginato MJ: Hypoxia/HIF1alpha induces lapatinib resistance in ERBB2-positive breast cancer cells via regulation of dusp2. Oncotarget 2014
195.
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, Fecher LA, Millward M, McArthur GA, Hwu P, Gonzalez R, Ott PA, Long GV, Gardner OS, Ouellet D, Xu Y, DeMarini DJ, Le NT, Patel K, Lewis KD. Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic braf-mutant cutaneous melanoma previously treated with or without a braf inhibitor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31:482–9.CrossRef
196.
Aird KM, Allensworth JL, Batinic-Haberle I, Lyerly HK, Dewhirst MW, Devi GR. ERBB1/2 tyrosine kinase inhibitor mediates oxidative stress-induced apoptosis in inflammatory breast cancer cells. Breast Cancer Res Treat. 2011;132:109–19.PubMedPubMedCentralCrossRef
197.
Shell SA, Lyass L, Trusk PB, Pry KJ, Wappel RL, Bacus SS. Activation of ampk is necessary for killing cancer cells and sparing cardiac cells. Cell Cycle. 2008;7:1769–75.PubMedCrossRef
198.
Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12:913–22.PubMedCrossRef
199.
Contreras CM, Gurumurthy S, Haynie JM, Shirley LJ, Akbay EA, Wingo SN, Schorge JO, Broaddus RR, Wong KK, Bardeesy N, Castrillon DH. Loss of lkb1 provokes highly invasive endometrial adenocarcinomas. Cancer Res. 2008;68:759–66.PubMedCrossRef
200.
Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D. The identification and characterization of breast cancer ctcs competent for brain metastasis. Sci Transl Med. 2013;5:180ra148.CrossRef
201.
Naggi A, Casu B, Perez M, Torri G, Cassinelli G, Penco S, Pisano C, Giannini G, Ishai-Michaeli R, Vlodavsky I. Modulation of the heparanase-inhibiting activity of heparin through selective desulfation, graded n-acetylation, and glycol splitting. J Biol Chem. 2005;280:12103–13.PubMedCrossRef
202.
Ritchie JP, Ramani VC, Ren Y, Naggi A, Torri G, Casu B, Penco S, Pisano C, Carminati P, Tortoreto M, Zunino F, Vlodavsky I, Sanderson RD, Yang Y. Sst0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clinical cancer research: an official journal of the American Association for Cancer Research. 2011;17:1382–93.CrossRef
203.
Zhang L, Ngo JA, Wetzel MD, Marchetti D. Heparanase mediates a novel mechanism in lapatinib-resistant brain metastatic breast cancer. Neoplasia. 2015;17:101–13.PubMedPubMedCentralCrossRef
204.
Purushothaman A, Chen L, Yang Y, Sanderson RD. Heparanase stimulation of protease expression implicates it as a master regulator of the aggressive tumor phenotype in myeloma. J Biol Chem. 2008;283:32628–36.PubMedPubMedCentralCrossRef
205.
Beauvais DM, Rapraeger AC. Syndecans in tumor cell adhesion and signaling. Reproductive biology and endocrinology : RB&E. 2004;2:3.CrossRef
206.
Reiland J, Kempf D, Roy M, Denkins Y, Marchetti D: Fgf2 binding, signaling, and angiogenesis are modulated by heparanase in metastatic melanoma cells. Neoplasia (New York, NY) 2006;8:596–606.
207.
Komurov K, Tseng JT, Muller M, Seviour EG, Moss TJ, Yang L, Nagrath D, Ram PT. The glucose-deprivation network counteracts lapatinib-induced toxicity in resistant ERBB2-positive breast cancer cells. Mol Syst Biol. 2012;8:596.PubMedPubMedCentralCrossRef
208.
Sonoda H, Inoue H, Ogawa K, Utsunomiya T, Masuda TA, Mori M. Significance of skp2 expression in primary breast cancer. Clin Cancer Res. 2006;12:1215–20.PubMedCrossRef
209.
Signoretti S, Di Marcotullio L, Richardson A, Ramaswamy S, Isaac B, Rue M, Monti F, Loda M, Pagano M. Oncogenic role of the ubiquitin ligase subunit skp2 in human breast cancer. J Clin Invest. 2002;110:633–41.PubMedPubMedCentralCrossRef
210.
Besson A, Hwang HC, Cicero S, Donovan SL, Gurian-West M, Johnson D, Clurman BE, Dyer MA, Roberts JM. Discovery of an oncogenic activity in p27kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 2007;21:1731–46.PubMedPubMedCentralCrossRef
211.
Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee J-H, Ciarallo S, Catzavelos C, Beniston R, Franssen E, Slingerland JM. Pkb/akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated g1 arrest. Nat Med. 2002;8:1153–60.PubMedCrossRef
212.
Denicourt C, Saenz CC, Datnow B, Cui X-S, Dowdy SF. Relocalized p27kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma. Cancer Res. 2007;67:9238–43.PubMedCrossRef
213.
Min YH, Cheong J-W, Kim JY, Eom JI, Lee ST, Hahn JS, Ko YW, Lee MH. Cytoplasmic mislocalization of p27kip1 protein is associated with constitutive phosphorylation of Akt or protein kinase b and poor prognosis in acute myelogenous leukemia. Cancer Res. 2004;64:5225–31.PubMedCrossRef
214.
Rosen DG, Yang G, Cai KQ, Bast RC, Gershenson DM, Silva EG, Liu J. Subcellular localization of p27kip1 expression predicts poor prognosis in human ovarian cancer. Clinical cancer research: an official journal of the American Association for Cancer Research. 2005;11:632–7.
215.
Andre F, Conforti R, Moeder CB, Mauguen A, Arnedos M, Berrada N, Delaloge S, Tomasic G, Spielmann M, Esteva FJ, Rimm DL, Michiels S. Association between the nuclear to cytoplasmic ratio of p27 and the efficacy of adjuvant polychemotherapy in early breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 2012;23:2059–64.CrossRef
216.
Zhao H, Faltermeier CM, Mendelsohn L, Porter PL, Clurman BE, Roberts JM. Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy. Oncotarget. 2014;5:12704–14.PubMedCrossRef
217.
Andrés-Pons A, Gil A, Oliver MD, Sotelo N-S, Pulido R. Cytoplasmic p27kip1 counteracts the pro-apoptotic function of the open conformation of PTEN by retention and destabilization of PTEN outside of the nucleus. Cell Signal. 2012;24:577–87.PubMedCrossRef
218.
219.
Jhaveri K, Ochiana SO, Dunphy MP, Gerecitano JF, Corben AD, Peter RI, Janjigian YY, Gomes-DaGama EM, Koren 3rd J, Modi S, Chiosis G. Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions. Expert Opin Investig Drugs. 2014;23:611–28.PubMedPubMedCentralCrossRef
220.
Huang W, Ye M, Zhang LR, Wu QD, Zhang M, Xu JH, Zheng W. Fw-04-806 inhibits proliferation and induces apoptosis in human breast cancer cells by binding to n-terminus of hsp90 and disrupting hsp90-cdc37 complex formation. Mol Cancer. 2014;13:150.PubMedPubMedCentralCrossRef
221.
Giuliano M, Hu H, Wang YC, Fu X, Nardone A, Herrera S, Mao S, Contreras A, Gutierrez C, Tao W, Hilsenbeck SG, De Angelis C, Wang NJ, Heiser L, Gray JW, Lopez-Tarruella S, Pavlick A, Trivedi MV, Chamness GC, Chang JC, Osborne CK, Rimawi MF, Schiff R: Upregulation of ER signaling as an adaptive mechanism of cell survival in HER2-positive breast tumors treated with anti-HER2 therapy. Clin Cancer Res 2015
222.
Rimawi MF, Wiechmann LS, Wang Y-C, Huang C, Migliaccio I, Wu M-F, Gutierrez C, Hilsenbeck SG, Arpino G, Massarweh S, Ward R, Soliz R, Osborne CK, Schiff R. Reduced dose and intermittent treatment with lapatinib and trastuzumab for potent blockade of the HER pathway in HER2/neu-overexpressing breast tumor xenografts. Clinical cancer research : an official journal of the American Association for Cancer Research. 2011;17:1351–61.CrossRef
223.
Arpino G, Gutierrez C, Weiss H, Rimawi M, Massarweh S, Bharwani L, De Placido S, Osborne CK, Schiff R. Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst. 2007;99:694–705.PubMedCrossRef
224.
Johnston S, Pippen J, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009;27:5538–46.CrossRef
225.
Schwartzberg LS, Schwarzberg LS, Franco SX, Florance A, O'Rourke L, Maltzman J, Johnston S. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010;15:122–9.PubMedPubMedCentralCrossRef
226.
Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, Schiff R, Osborne CK, Chang JC. Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: Tbcrc 006. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31:1726–31.CrossRef
227.
Bailey ST, Miron PL, Choi YJ, Kochupurakkal B, Maulik G, Rodig SJ, Tian R, Foley KM, Bowman T, Miron A, Brown M, Iglehart JD, Biswas DK. Nf-kappab activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth. Mol Cancer Res. 2014;12:408–20.PubMedCrossRef
228.
Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin Jr AS. Selective activation of nf-kappa b subunits in human breast cancer: potential roles for NF-kappa b2/p52 and for bcl-3. Oncogene. 2000;19:1123–31.
229.
Biswas DK, Shi Q, Baily S, Strickland I, Ghosh S, Pardee AB, Iglehart JD. NF-kappa b activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A. 2004;101:10137–42.PubMedPubMedCentralCrossRef
230.
Singh S, Shi Q, Bailey ST, Palczewski MJ, Pardee AB, Iglehart JD, Biswas DK. Nuclear factor-kappab activation: a molecular therapeutic target for estrogen receptor-negative and epidermal growth factor receptor family receptor-positive human breast cancer. Mol Cancer Ther. 2007;6:1973–82.PubMedCrossRef
231.
Wetterskog D, Shiu KK, Chong I, Meijer T, Mackay A, Lambros M, Cunningham D, Reis-Filho JS, Lord CJ, Ashworth A. Identification of novel determinants of resistance to lapatinib in ERBB2-amplified cancers. Oncogene. 2014;33:966–76.PubMedCrossRef
232.
Xia W, Bacus S, Husain I, Liu L, Zhao S, Liu Z, Moseley MA, Thompson JW, Chen FL, Koch KM, Spector NL. Resistance to ERBB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of rela. Mol Cancer Ther. 2010;9:292–9.PubMedCrossRef
233.
Ma C: Lapatinib inhibits the activation of nf-κb through reducing phosphorylation of iκb-α in breast cancer cells. Oncology Reports 2012
234.
235.
Polli JW, Olson KL, Chism JP, John-Williams LS, Yeager RL, Woodard SM, Otto V, Castellino S, Demby VE. An unexpected synergist role of p-glycoprotein and breast cancer resistance protein on the central nervous system penetration of the tyrosine kinase inhibitor lapatinib (n-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino }methyl)-2-furyl]-4-quinazolinamine; gw572016). Drug Metab Dispos. 2009;37:439–42.PubMedCrossRef
236.
Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby Jr CR, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW. Lapatinib (tykerb, gw572016) reverses multidrug resistance in cancer cells by inhibiting the activity of atp-binding cassette subfamily b member 1 and g member 2. Cancer Res. 2008;68:7905–14.
237.
Maeng H-J, Kim E-S, Chough C, Joung M, Lim JW, Shim C-K, Shim W-S. Addition of amino acid moieties to lapatinib increases the anti-cancer effect via amino acid transporters. Biopharm Drug Dispos. 2014;35:60–9.PubMedCrossRef
238.
Scaltriti M, Verma C, Guzman M, Jimenez J, Parra JL, Pedersen K, Smith DJ, Landolfi S, Ramon y Cajal S, Arribas J, Baselga J Lapatinib, a her2 tyrosine kinase inhibitor, induces stabilization and accumulation of her2 and potentiates trastuzumab-dependent cell cytotoxicity. Oncogene 2009;28:803–814.
239.
Kang SH, Kang KW, Kim K-H, Kwon B, Kim S-K, Lee H-Y, Kong S-Y, Lee ES, Jang S-G, Yoo BC. Upregulated HSP27 in human breast cancer cells reduces herceptin susceptibility by increasing HER2 protein stability. BMC Cancer. 2008;8:286.PubMedPubMedCentralCrossRef
240.
Rani S, Corcoran C, Shiels L, Germano S, Breslin S, Madden S, McDermott MS, Browne BC, O'Donovan N, Crown J, Gogarty M, Byrne AT, O'Driscoll L. Neuromedin u: a candidate biomarker and therapeutic target to predict and overcome resistance to HER-tyrosine kinase inhibitors. Cancer Res. 2014;74:3821–33.PubMedCrossRef
Metadata
Title
Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms
Authors
Huiping Shi
Weili Zhang
Qiaoming Zhi
Min Jiang
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5467-2

Other articles of this Issue 12/2016

Tumor Biology 12/2016 Go to the issue

Original Article

E-cadherin mediates adhesion of Aspergillus fumigatus to non-small cell lung cancer cells

Original Article

Notch3 negatively regulates chemoresistance in breast cancers

Review

The role of stem cells in benign tumors

Original Article

A promising prediction model for survival in gallbladder carcinoma patients: pretreatment prognostic nutrient index

Original Article

Methylation in promoter regions of PITX2 and RASSF1A genes in association with clinicopathological features in breast cancer patients

Review

Regulation of autophagy by Ca2+
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits