Top

Published in:

01-09-2011 | Preclinical study

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells

Authors: Caroline Brünner-Kubath, Waheed Shabbir, Victoria Saferding, Renate Wagner, Christian F. Singer, Peter Valent, Walter Berger, Brigitte Marian, Christoph C. Zielinski, Michael Grusch, Thomas W. Grunt

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

Resistance against first and second generation (irreversible) ErbB inhibitors is an unsolved problem in clinical oncology. The purpose of this study was to examine the effects of the irreversible ErbB inhibitors pelitinib and canertinib on growth of breast and ovarian cancer cells. Although in vitro growth-inhibitory effects of both drugs exceeded by far the effects of all reversible ErbB blockers tested (lapatinib, erlotinib, and gefitinib), complete growth inhibition was usually not reached. To define the mechanism of resistance, we examined downstream signaling pathways in drug-exposed cells by Western blot analysis. Although ErbB phosphorylation was reduced by pelitinib and canertinib, activation of the AKT/mTOR pathway remained essentially unaltered in drug-resistant cells. Correspondingly, transfection of tumor cells with constitutively activated AKT was found to promote resistance against all ErbB inhibitors tested, whereas dominant negative AKT reinstalled sensitivity in drug-resistant cells. In a next step, we applied PI3K/AKT/mTOR blockers including the dual PI3K/mTOR kinase inhibitor NVP-BEZ235. These agents were found to cooperate with pelitinib and canertinib in producing in vitro growth inhibition in cancer cells resistant against ErbB-targeting drugs. In conclusion, our data show that ErbB drug-refractory activation of the PI3K/AKT/mTOR pathway plays a crucial role in resistance against classical and second-generation irreversible ErbB inhibitors, and NVP-BEZ235 can override this form of resistance against pelitinib and canertinib.

Available only for authorised users

Yarden Y, Baselga J, Miles D (2004) Molecular approach to breast cancer treatment. Semin Oncol 31(Suppl 10):6–13PubMedCrossRef

Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516PubMedCrossRef

Geyer CE, Forster J, Lindquist D et al (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355:2733–2743PubMedCrossRef

Ocaña A, Amir E (2009) Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions. Cancer Treat Rev 35:685–691PubMedCrossRef

Rabindran SK, Discafani CM, Rosfjord EC et al (2004) Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958–3965PubMedCrossRef

Ocaña A, Serrano R, Calero R, Pandiella A (2009) Novel tyrosine kinase inhibitors in the treatment of cancer. Curr Drug Targets 10:575–576PubMedCrossRef

Testa JR, Bellacosa A (2001) AKT plays a central role in tumourigenesis. Proc Natl Acad Sci USA 98:10983–10985PubMedCrossRef

Maurer M, Su T, Saal LH et al (2009) 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma. Cancer Res 69:6299–6306PubMedCrossRef

Moasser MM, Basso A, Averbuch SD, Rosen N (2001) The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184–7188PubMed

10.

Moulder SL, Yakes FM, Muthuswamy SK, Bianco R, Simpson JF, Arteaga CL (2001) 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 61:8887–8895PubMed

11.

Maiello MR, D’Alessio A, De Luca A et al (2007) AZD3409 inhibits the growth of breast cancer cells with intrinsic resistance to the EGFR tyrosine kinase inhibitor gefitinib. Breast Cancer Res Treat 102:275–282PubMedCrossRef

12.

Wissner A, Overbeek E, Reich MF et al (2003) Synthesis and structure-activity relationships of 6, 7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 46:49–63PubMedCrossRef

13.

Nunes M, Shi C, Greenberger LM (2004) Phosphorylation of extracellular signal-regulated kinase 1 and 2, protein kinase B, and signal transducer and activator of transcription 3 are differently inhibited by an epidermal growth factor receptor inhibitor, EKB-569, in tumor cells and normal human keratinocytes. Mol Cancer Ther 3:21–27PubMedCrossRef

14.

Wissner A, Mansour TS (2008) The development of HKI-272 and related compounds for the treatment of cancer. Arch Pharm 341:465–477CrossRef

15.

Wood ER, Truesdale AT, McDonald OB et al (2004) A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells. Cancer Res 64:6652–6659PubMedCrossRef

16.

Sequist LV (2007) Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Oncologist 12:325–330PubMedCrossRef

17.

Campos S, Hamid O, Seiden MV et al (2005) Multicenter, randomized phase II trial of oral CI-1033 for previously treated advanced ovarian cancer. J Clin Oncol 23:5597–5604PubMedCrossRef

18.

Laheru D, Croghan G, Bukowski R et al (2008) A phase I study of EKB-569 in combination with capecitabine in patients with advanced colorectal cancer. Clin Cancer Res 14:5602–5609PubMedCrossRef

19.

Grunt TW, Dittrich E, Offterdinger M, Schneider SM, Dittrich C, Huber H (1998) Effects of retinoic acid and fenretinide on the c-erbB-2 expression, growth and cisplatin sensitivity of breast cancer cells. Br J Cancer 78:79–87PubMedCrossRef

20.

Grunt TW, Puckmair K, Tomek K, Kainz B, Gaiger A (2005) An EGF receptor inhibitor induces RAR-beta expression in breast and ovarian cancer cells. Biochem Biophys Res Commun 329:1253–1259PubMedCrossRef

21.

Namikawa K, Honma M, Abe K et al (2000) Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J Neurosci 20:2875–2886PubMed

22.

Longo PG, Laurenti L, Gobessi S et al (2007) The Akt signaling pathway determines the different proliferative capacity of chronic lymphocytic leukemia B-cells from patients with progressive and stable disease. Leukemia 21:110–120PubMedCrossRef

23.

Bellacosa A, Chan TO, Ahmed NN et al (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17:313–325PubMedCrossRef

24.

Burris HA III, Hurwitz HI, Dees EC et al (2005) Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 23:5305–5313PubMedCrossRef

25.

Wang YC, Kulp SK, Wang D et al (2008) Targeting endoplasmic reticulum stress and Akt with OSU-03012 and gefitinib or erlotinib to overcome resistance to epidermal growth factor receptor inhibitors. Cancer Res 68:2820–2830PubMedCrossRef

26.

Grunt TW, Tomek K, Wagner R et al (2007) Upregulation of retinoic acid receptor-beta by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways. J Cell Physiol 211:803–815PubMedCrossRef

27.

Vogel CL, Reddy JC, Reyno LM (2005) Efficacy of trastuzumab. Cancer Res 65:2044PubMedCrossRef

28.

Neve RM, Chin K, Fridlyand J et al (2006) A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell 10:515–527PubMedCrossRef

29.

Tzahar E, Waterman H, Chen X et al (1996) A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276–5287PubMed

30.

Troyer KL, Lee DC (2001) Regulation of mouse mammary gland development and tumorigenesis by the ERBB signaling network. J Mammary Gland Biol Neoplasia 6:7–21PubMedCrossRef

31.

Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst 93:1852–1857PubMedCrossRef

32.

Jones HE, Goddard L, Gee JM et al (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedCrossRef

33.

Serra V, Markman B, Scaltriti M et al (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022–8030PubMedCrossRef

34.

Sarbassov DD, Ali SM, Sengupta S et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168PubMedCrossRef

35.

Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37(Pt 1):217–222PubMedCrossRef

36.

Nelson JM, Fry DW (2001) Akt, MAPK (Erk1/2), and p38 act in concert to promote apoptosis in response to ErbB receptor family inhibition. J Biol Chem 276:14842–14847PubMedCrossRef

37.

Crespo A, Zhang X, Fernández A (2008) Redesigning kinase inhibitors to enhance specificity. J Med Chem 51:4890–4898PubMedCrossRef

38.

Slichenmyer WJ, Elliott WL, Fry DW (2001) CI-1033, a pan-erbB tyrosine kinase inhibitor. Semin Oncol 28:80–85PubMedCrossRef

39.

Kumar A, Petri ET, Halmos B, Boggon TJ (2008) Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol 26:1742–1751PubMedCrossRef

40.

Grunt TW, Wagner R, Grusch M et al (2009) Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem Biophys Res Commun 385:454–459PubMedCrossRef

41.

Sergina NV, Rausch M, Wang D et al (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441PubMedCrossRef

42.

Hollestelle A, Elstrodt F, Nagel JH, Kallemeijn WW, Schutte M (2007) Phosphatidylinositol-3-OH kinase or RAS pathway mutations in human breast cancer cell lines. Mol Cancer Res 5:195–201PubMedCrossRef

43.

García JM, Silva J, Peña C et al (2004) Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 41:117–124PubMedCrossRef

44.

Wang X, Trotman LC, Koppie T et al (2007) NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 128:129–139PubMedCrossRef

45.

She QB, Solit D, Basso A, Moasser MM (2003) Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res 9:4340–4346PubMed

46.

Magné N, Fischel JL, Dubreuil A et al (2002) Influence of epidermal growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway status of tumour cells on the antiproliferative effect of ZD1839 (“Iressa”). Br J Cancer 86:1518–1523PubMedCrossRef

47.

Yokoyama H, Ikehara Y, Kodera Y et al (2006) Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasis. Br J Cancer 95:1504–1513PubMedCrossRef

48.

Normanno N, De Luca A, Maiello MR et al (2006) The MEK/MAPK pathway is involved in the resistance of breast cancer cells to the EGFR tyrosine kinase inhibitor gefitinib. J Cell Physiol 207:420–427PubMedCrossRef

49.

Normanno N, Campiglio M, Maiello MR et al (2008) Breast cancer cells with acquired resistance to the EGFR tyrosine kinase inhibitor gefitinib show persistent activation of MAPK signaling. Breast Cancer Res Treat 112:25–33PubMedCrossRef

50.

Campiglio M, Locatelli A, Olgiati C et al (2004) Inhibition of proliferation and induction of apoptosis in breast cancer cells by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (‘Iressa’) is independent of EGFR expression level. J Cell Physiol 198:259–268PubMedCrossRef

51.

Yamasaki F, Zhang D, Bartholomeusz C et al (2007) Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity. Mol Cancer Ther 6:2168–2177PubMedCrossRef

52.

Rodriguez-Viciana P, Warne PH, Dhand R et al (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532PubMedCrossRef

53.

Mirzoeva OK, Das D, Heiser LM et al (2009) Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res 69:565–572PubMedCrossRef

54.

Samuels Y, Diaz LA Jr, Schmidt-Kittler O et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573PubMedCrossRef

55.

Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091PubMedCrossRef

56.

Vasudevan KM, Barbie DA, Davies MA et al (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21–32PubMedCrossRef

Title: The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells
Authors: Caroline Brünner-Kubath
Waheed Shabbir
Victoria Saferding
Renate Wagner
Christian F. Singer
Peter Valent
Walter Berger
Brigitte Marian
Christoph C. Zielinski
Michael Grusch
Thomas W. Grunt
Publication date: 01-09-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-010-1232-1

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

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

The relationship between bone mineral density and mammographic density in Korean women: The Healthy Twin study

A nomogram to predict survival time in women starting first-line chemotherapy for advanced breast cancer

Nuclear co-localization and functional interaction of COX-2 and HIF-1α characterize bone metastasis of human breast carcinoma

Association between two polymorphisms of CD166/ALCAM gene and breast cancer risk in Chinese women

Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression

PIK3CA mutations rarely demonstrate genotypic intratumoral heterogeneity and are selected for in breast cancer progression

Keynote webinar | Spotlight on antibody–drug conjugates in cancer