Top

Published in:

01-12-2012 | PRECLINICAL STUDIES

The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines

Authors: Hyun-Jin Nam, Hwang-Phill Kim, Young-Kwang Yoon, Sang-Hyun Song, Ah-Rum Min, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang

Published in: Investigational New Drugs | Issue 6/2012

Summary

Biliary tract cancer (BTC) is associated with poor survival and unresponsiveness to chemotherapy. Targeted therapies for BTC have been studied, and HER family members are promising therapeutic targets in BTC. In this study, we evaluated the efficacy of PF00299804, an irreversible pan-HER inhibitor, in eight BTC cell lines alone or combined with gemcitabine. PF00299804 potently inhibited the growth of two cell lines (SNU308 and SNU478) out of the eight BTC cell lines as a single agent. PF00299804 blocked HER family and downstream signaling pathways, inducing G1 arrest or apoptosis. Moreover, PF00299804 exerted synergistic effects with gemcitabine in seven of the eight BTC cell lines, possibly through the regulation of the genes involved in the response to gemcitabine, such as TS (thymidylate synthase), RRM1 (ribonucleotide reductase), and MAGEH1, which is negatively correlated with gemcitabine sensitivity. Our results support the need for further study of PF00299804 alone or combined with gemcitabine for the treatment of BTC.

Available only for authorised users

de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM (1999) Biliary tract cancers. N Engl J Med 341:1368–1378PubMedCrossRef

Wiedmann M, Feisthammel J, Bluthner T, Tannapfel A, Kamenz T, Kluge A, Mossner J, Caca K (2006) Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib. Anticancer Drugs 17:783–795PubMedCrossRef

Kawamoto T, Krishnamurthy S, Tarco E, Trivedi S, Wistuba II, Li D, Roa I, Roa JC, Thomas MB (2007) HER Receptor family: novel candidate for targeted therapy for gallbladder and extrahepatic bile duct cancer. Gastrointest Cancer Res 1:221–227PubMed

Tonini G, Frato ME, Vincenzi B, Santini D (2010) Chemotherapy in biliary tract cancer. Eur Rev Med Pharmacol Sci 14:371–374PubMed

Tonini G, Virzi V, Fratto ME, Vincenzi B, Santini D (2009) Targeted therapy in biliary tract cancer: 2009 update. Future Oncol 5:1675–1684PubMedCrossRef

Harder J, Waiz O, Otto F, Geissler M, Olschewski M, Weinhold B, Blum HE, Schmitt-Graeff A, Opitz OG (2009) EGFR and HER2 expression in advanced biliary tract cancer. World J Gastroenterol 15:4511–4517PubMedCrossRef

Herberger B, Berger W, Puhalla H, Schmid K, Novak S, Brandstetter A, Pirker C, Gruenberger T, Filipits M (2009) Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells. Mol Cancer Ther 8:1547–1556PubMedCrossRef

Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, Hirohashi S, Shibata T (2008) Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer 98:418–425PubMedCrossRef

Ito Y, Takeda T, Sasaki Y, Sakon M, Yamada T, Ishiguro S, Imaoka S, Tsujimoto M, Higashiyama S, Monden M, Matsuura N (2001) Expression and clinical significance of the erbB family in intrahepatic cholangiocellular carcinoma. Pathol Res Pract 197:95–100PubMedCrossRef

10.

Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A (2005) Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol 206:356–365PubMedCrossRef

11.

Gwak GY, Yoon JH, Shin CM, Ahn YJ, Chung JK, Kim YA, Kim TY, Lee HS (2005) Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol 131:649–652PubMedCrossRef

12.

Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W, Venesio T, Capussotti L, Risio M, Aglietta M (2006) Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 12:1680–1685PubMedCrossRef

13.

Pawson T (2004) Specificity in signal transduction: from phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell 116:191–203PubMedCrossRef

14.

Mass RD (2004) The HER receptor family: a rich target for therapeutic development. Int J Radiat Oncol Biol Phys 58:932–940PubMedCrossRef

15.

Arteaga CL (2001) The epidermal growth factor receptor: from mutant oncogene in nonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol 19:32S–40SPubMed

16.

Pignochino Y, Sarotto I, Peraldo-Neia C, Penachioni JY, Cavalloni G, Migliardi G, Casorzo L, Chiorino G, Risio M, Bardelli A, Aglietta M, Leone F (2010) Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer 10:631PubMedCrossRef

17.

Xu L, Hausmann M, Dietmaier W, Kellermeier S, Pesch T, Stieber-Gunckel M, Lippert E, Klebl F, Rogler G (2010) Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines. BMC Cancer 10:302PubMedCrossRef

18.

Yoshikawa D, Ojima H, Kokubu A, Ochiya T, Kasai S, Hirohashi S, Shibata T (2009) Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. Br J Cancer 100:1257–1266PubMedCrossRef

19.

Hidalgo M, Amador ML, Jimeno A, Mezzadra H, Patel P, Chan A, Nielsen ME, Maitra A, Altiok S (2006) Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration. Mol Cancer Ther 5:1895–1903PubMedCrossRef

20.

Ariyama H, Qin B, Baba E, Tanaka R, Mitsugi K, Harada M, Nakano S (2006) Gefitinib, a selective EGFR tyrosine kinase inhibitor, induces apoptosis through activation of Bax in human gallbladder adenocarcinoma cells. J Cell Biochem 97:724–734PubMedCrossRef

21.

Kiguchi K, Ruffino L, Kawamoto T, Ajiki T, Digiovanni J (2005) Chemopreventive and therapeutic efficacy of orally active tyrosine kinase inhibitors in a transgenic mouse model of gallbladder carcinoma. Clin Cancer Res 11:5572–5580PubMedCrossRef

22.

Jimeno A, Rubio-Viqueira B, Amador ML, Oppenheimer D, Bouraoud N, Kulesza P, Sebastiani V, Maitra A, Hidalgo M (2005) Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 65:3003–3010PubMed

23.

Chang PY, Cheng MF, Lee HS, Hsieh CB, Yao NS (2010) Preliminary experience of cetuximab in the treatment of advanced-stage biliary tract cancer. Onkologie 33:45–47PubMedCrossRef

24.

Tada M, Nakai Y, Sasaki T, Hamada T, Nagano R, Mohri D, Miyabayashi K, Yamamoto K, Kogure H, Kawakubo K, Ito Y, Yamamoto N, Sasahira N, Hirano K, Ijichi H, Tateishi K, Isayama H, Omata M, Koike K (2011) Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers. World J Clin Oncol 2:158–163PubMedCrossRef

25.

Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, Philip PA, Picus J, Yong WP, Horvath L, Van Hazel G, Erlichman CE, Holen KD (2010) Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study. J Clin Oncol 28:3491–3497PubMedCrossRef

26.

Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, Donehower RC, Fitch T, Picus J, Erlichman C (2006) Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24:3069–3074PubMedCrossRef

27.

Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, Kindler HL, Iqbal S, Longmate J, Mack PC, Lurje G, Gandour-Edwards R, Dancey J, Gandara DR (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64:777–783PubMedCrossRef

28.

Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, Zhao F, Vincent PW, Naumov GN, Bradner JE, Althaus IW, Gandhi L, Shapiro GI, Nelson JM, Heymach JV, Meyerson M, Wong KK, Janne PA (2007) PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res 67:11924–11932PubMedCrossRef

29.

Gonzales AJ, Hook KE, Althaus IW, Ellis PA, Trachet E, Delaney AM, Harvey PJ, Ellis TA, Amato DM, Nelson JM, Fry DW, Zhu T, Loi CM, Fakhoury SA, Schlosser KM, Sexton KE, Winters RT, Reed JE, Bridges AJ, Lettiere DJ, Baker DA, Yang J, Lee HT, Tecle H, Vincent PW (2008) Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther 7:1880–1889PubMedCrossRef

30.

Ercan D, Zejnullahu K, Yonesaka K, Xiao Y, Capelletti M, Rogers A, Lifshits E, Brown A, Lee C, Christensen JG, Kwiatkowski DJ, Engelman JA, Janne PA (2010) Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor. Oncogene 29:2346–2356PubMedCrossRef

31.

Turke AB, Zejnullahu K, Wu YL, Song Y, Dias-Santagata D, Lifshits E, Toschi L, Rogers A, Mok T, Sequist L, Lindeman NI, Murphy C, Akhavanfard S, Yeap BY, Xiao Y, Capelletti M, Iafrate AJ, Lee C, Christensen JG, Engelman JA, Janne PA (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88PubMedCrossRef

32.

Ku JL, Park JG (2005) Biology of SNU cell lines. Cancer Res Treat 37:1–19PubMedCrossRef

33.

Ku JL, Yoon KA, Kim IJ, Kim WH, Jang JY, Suh KS, Kim SW, Park YH, Hwang JH, Yoon YB, Park JG (2002) Establishment and characterisation of six human biliary tract cancer cell lines. Br J Cancer 87:187–193PubMedCrossRef

34.

Nam HJ, Kim HP, Yoon YK, Hur HS, Song SH, Kim MS, Lee GS, Han SW, Im SA, Kim TY, Oh DY, Bang YJ (2011) Antitumor activity of HM781-36B, an irreversible Pan-HER inhibitor, alone or in combination with cytotoxic chemotherapeutic agents in gastric cancer. Cancer Lett 302:155–165PubMedCrossRef

35.

Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55PubMedCrossRef

36.

Erlichman C, Boerner SA, Hallgren CG, Spieker R, Wang XY, James CD, Scheffer GL, Maliepaard M, Ross DD, Bible KC, Kaufmann SH (2001) The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux. Cancer Res 61:739–748PubMed

37.

Han SW, Kim TY, Hwang PG, Jeong S, Kim J, Choi IS, Oh DY, Kim JH, Kim DW, Chung DH, Im SA, Kim YT, Lee JS, Heo DS, Bang YJ, Kim NK (2005) Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493–2501PubMedCrossRef

38.

Lee KW, Kim JH, Park JH, Kim HP, Song SH, Kim SG, Kim TY, Jong HS, Jung KH, Im SA, Kim NK, Bang YJ (2006) Antitumor activity of SK-7041, a novel histone deacetylase inhibitor, in human lung and breast cancer cells. Anticancer Res 26:3429–3438PubMed

39.

Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H (2005) Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73PubMedCrossRef

40.

Yoon YK, Kim HP, Han SW, Hur HS, Test YOh (2009) article sample title placed here. Mol Cancer Ther 8:2526–2536PubMedCrossRef

41.

Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, Zander T, Seeger JM, Weiss J, Fischer F, Frommolt P, Michel K, Peifer M, Mermel C, Girard L, Peyton M, Gazdar AF, Minna JD, Garraway LA, Kashkar H, Pao W, Meyerson M, Thomas RK (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256–3261PubMedCrossRef

42.

Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, Zakowski MF, Heelan RT, Kris MG, Varmus HE (2005) KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17PubMedCrossRef

43.

Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22PubMedCrossRef

44.

Kadota M, Sato M, Duncan B, Ooshima A, Yang HH, Diaz-Meyer N, Gere S, Kageyama S, Fukuoka J, Nagata T, Tsukada K, Dunn BK, Wakefield LM, Lee MP (2009) Identification of novel gene amplifications in breast cancer and coexistence of gene amplification with an activating mutation of PIK3CA. Cancer Res 69:7357–7365PubMedCrossRef

45.

Yoon YK, Kim HP, Han SW, Test YOh (2010) article sample title placed here. Mol Carcinog 49:353–362PubMedCrossRef

46.

Nabeya Y, Suzuki T, Furuya A, Koide N, Ohkoshi M, Takiguchi M, Ochiai T, Matsubara H, Hiwasa T (2011) Calpain regulates thymidylate synthase-5-fluoro-dUMP complex levels associated with response to 5-fluorouracil in gastric cancer cells. Cancer Sci 102:1509–1515PubMedCrossRef

47.

Komori S, Osada S, Mori R, Matsui S, Sanada Y, Tomita H, Tokuyama Y, Takahashi T, Yamaguchi K, Yoshida K (2010) Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer. Pancreas 39:1284–1292PubMedCrossRef

48.

Shi Y, Chen L, Li J, Lu YL, Jiao SC (2010) Expression and predictive role of excision repair cross complementation group 1, ribonucleotide reductase subunit M1, and beta-tubulin3 in postoperative patients with non-small cell lung cancer receiving adjuvant chemotherapy. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 32:375–382PubMed

49.

Ferrandina G, Mey V, Nannizzi S, Ricciardi S, Petrillo M, Ferlini C, Danesi R, Scambia G, Del Tacca M (2010) Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. Cancer Chemother Pharmacol 65:679–686PubMedCrossRef

50.

Fujita H, Ohuchida K, Mizumoto K, Itaba S, Ito T, Nakata K, Yu J, Kayashima T, Souzaki R, Tajiri T, Manabe T, Ohtsuka T, Tanaka M (2010) Gene expression levels as predictive markers of outcome in pancreatic cancer after gemcitabine-based adjuvant chemotherapy. Neoplasia 12:807–817PubMed

51.

Ohhashi S, Ohuchida K, Mizumoto K, Fujita H, Egami T, Yu J, Toma H, Sadatomi S, Nagai E, Tanaka M (2008) Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer. Anticancer Res 28:2205–2212PubMed

52.

Ojima H, Yoshikawa D, Ino Y, Shimizu H, Miyamoto M, Kokubu A, Hiraoka N, Morofuji N, Kondo T, Onaya H, Okusaka T, Shimada K, Sakamoto Y, Esaki M, Nara S, Kosuge T, Hirohashi S, Kanai Y, Shibata T (2010) Establishment of six new human biliary tract carcinoma cell lines and identification of MAGEH1 as a candidate biomarker for predicting the efficacy of gemcitabine treatment. Cancer Sci 101:882–888PubMedCrossRef

53.

Weigt J, Malfertheiner P (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. Expert Rev Gastroenterol Hepatol 4:395–397PubMedCrossRef

54.

Wiedmann MW, Mossner J (2010) Molecular targeted therapy of biliary tract cancer–results of the first clinical studies. Curr Drug Targets 11:834–850PubMedCrossRef

55.

Safran H, Miner T, Resnick M, Dipetrillo T, McNulty B, Evans D, Joseph P, Plette A, Millis R, Sears D, Gutman N, Kennedy T (2008) Lapatinib/gemcitabine and lapatinib/gemcitabine/oxaliplatin: a phase I study for advanced pancreaticobiliary cancer. Am J Clin Oncol 31:140–144PubMedCrossRef

56.

Suda K, Murakami I, Katayama T, Tomizawa K, Osada H, Sekido Y, Maehara Y, Yatabe Y, Mitsudomi T (2010) Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin Cancer Res 16:5489–5498PubMedCrossRef

57.

Kim JW, Kim HP, Im SA, Kang S, Hur HS, Yoon YK, Oh DY, Kim JH, Lee DS, Kim TY, Bang YJ (2008) The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. Cancer Lett

58.

Kim HP, Yoon YK, Kim JW, Han SW, Hur HS, Park J, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY (2009) Lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, downregulates thymidylate synthase by inhibiting the nuclear translocation of EGFR and HER2. PLoS One 4:e5933PubMedCrossRef

59.

Li XD, Geng YT, Wu CP, Shen H, Sun J, Shu YQ, Yin YM (2010) Restoration of gefitinib efficacy following chemotherapy in a patient with metastatic non-small cell lung cancer. Onkologie 33:466–469PubMedCrossRef

60.

Pietras RJ, Poen JC, Gallardo D, Wongvipat PN, Lee HJ, Slamon DJ (1999) Monoclonal antibody to HER-2/neureceptor modulates repair of radiation-induced DNA damage and enhances radiosensitivity of human breast cancer cells overexpressing this oncogene. Cancer Res 59:1347–1355PubMed

61.

Osawa K (2009) Gene polymorphisms and chemotherapy in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi 12:837–840PubMed

Title: The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines
Authors: Hyun-Jin Nam
Hwang-Phill Kim
Young-Kwang Yoon
Sang-Hyun Song
Ah-Rum Min
Sae-Won Han
Seock-Ah Im
Tae-You Kim
Do-Youn Oh
Yung-Jue Bang
Publication date: 01-12-2012
Publisher: Springer US
Published in: Investigational New Drugs / Issue 6/2012
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-011-9782-6

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

Summary

Please log in to get access to this content

Other articles of this Issue 6/2012

Identification of cyclohexanone derivatives that act as catalytic inhibitors of topoisomerase I: effects on tamoxifen-resistant MCF-7 cancer cells

Predictive factors for response to treatment in patients with advanced renal cell carcinoma

Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy

Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas

Phase II study of bevacizumab and erlotinib in the treatment of advanced hepatocellular carcinoma patients with sorafenib-refractory disease

Quinones and halogenated monoterpenes of algal origin show anti-proliferative effects against breast cancer cells in vitro

Keynote webinar | Spotlight on antibody–drug conjugates in cancer