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Targeted therapy for biliary tract cancers

  • Topics
  • Update of chemotherapy for biliary tract cancer
  • Published:
Journal of Hepato-Biliary-Pancreatic Sciences

Abstract

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies, with a historically poor prognosis as a whole. Until recently, the development of effective therapeutics was hampered by the relatively low incidence, heterogeneity in patients and tumors, and correspondingly poor clinical trial enrollments. With the publication of the landmark phase III ABC-02 trial demonstrating the superiority of gemcitabine and cisplatin combination chemotherapy, the landscape changed for the development of new agents. Despite this progress, there are currently no approved targeted agents for BTC. This review will focus on recent developments in targeted therapeutics, directed against several key signaling pathways in BTC, including epidermal growth factor receptor, angiogenesis, and the mitogen-activated protein kinase pathway. Data from recent phase I and II trials will be discussed, along with a preview of upcoming trials involving targeted therapies.

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References

  1. Patel T. Cholangiocarcinoma—controversies and challenges. Nat Rev. 2011;8:189–200.

    CAS  Google Scholar 

  2. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. Semin Liver Dis. 2004;24:115–25.

    Article  PubMed  Google Scholar 

  3. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2006;15:1198–203.

    Article  PubMed  Google Scholar 

  4. West J, Wood H, Logan RF, Quinn M, Aithal GP. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br J Cancer. 2006;94:1751–8.

    Article  PubMed  CAS  Google Scholar 

  5. Welzel TM, Graubard BI, El-Serag HB, Shaib YH, Hsing AW, Davila JA, et al. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based case–control study. Clin Gastroenterol Hepatol. 2007;5:1221–8.

    Article  PubMed  Google Scholar 

  6. Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.

    Article  PubMed  Google Scholar 

  7. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology. 2001;3:1353–7.

    Article  Google Scholar 

  8. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New Engl J Med. 2010;362:1273–81.

    Article  PubMed  CAS  Google Scholar 

  9. Westgaard A, Tafjord S, Farstad IN, Cvancarova M, Eide TJ, Mathisen O, et al. Pancreatobiliary versus intestinal histologic type of differentiation is an independent prognostic factor in resected periampullary adenocarcinoma. BMC Cancer. 2008;8:170.

    Article  PubMed  Google Scholar 

  10. Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–40.

    Article  PubMed  CAS  Google Scholar 

  11. Neoptolemos JP MM CT, Valle JW, Palmer DH, Mcdonald A, et al. Ampullary cancer espac-3 (v2) trial: a multicenter, international open-label, randomized controlled phase iii trial of adjuvant chemotherapy versus observation in patients with adenocarcinoma of the ampulla of Vater. J Clin Oncol. 2011;29 (suppl; abstr LBA4006).

  12. Pignochino Y, Sarotto I, Peraldo-Neia C, Penachioni JY, Cavalloni G, Migliardi G, et al. Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder carcinomas. BMC Cancer. 2010;10:631.

    Article  PubMed  CAS  Google Scholar 

  13. Nonomura A, Ohta G, Nakanuma Y, Izumi R, Mizukami Y, Matsubara F, et al. Simultaneous detection of epidermal growth factor receptor (EGF-R), epidermal growth factor (EGF) and ras p21 in cholangiocarcinoma by an immunocytochemical method. Liver. 1988;8:157–66.

    PubMed  CAS  Google Scholar 

  14. Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T, Kasai S, et al. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br J Cancer. 2008;98:418–25.

    Article  PubMed  CAS  Google Scholar 

  15. Nakazawa K, Dobashi Y, Suzuki S, Fujii H, Takeda Y, Ooi A. Amplification and overexpression of c-erbB-2, epidermal growth factor receptor, and c-met in biliary tract cancers. J Pathol. 2005;206:356–65.

    Article  PubMed  CAS  Google Scholar 

  16. Gwak GY, Yoon JH, Shin CM, Ahn YJ, Chung JK, Kim YA, et al. Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinomas. J Cancer Res Clin Oncol. 2005;131:649–52.

    Article  PubMed  CAS  Google Scholar 

  17. Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R, Piacibello W, et al. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res. 2006;12:1680–5.

    Article  PubMed  CAS  Google Scholar 

  18. Werneburg NW, Yoon JH, Higuchi H, Gores GJ. Bile acids activate EGF receptor via a TGF-alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol. 2003;285:G31–6.

    CAS  Google Scholar 

  19. Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology. 2002;122:985–93.

    Article  PubMed  CAS  Google Scholar 

  20. Wiedmann M, Feisthammel J, Bluthner T, Tannapfel A, Kamenz T, Kluge A, et al. 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. Anti-cancer Drugs. 2006;17:783–95.

    Article  PubMed  CAS  Google Scholar 

  21. Hanada K, Tsuchida A, Iwao T, Eguchi N, Sasaki T, Morinaka K, et al. Gene mutations of K-ras in gallbladder mucosae and gallbladder carcinoma with an anomalous junction of the pancreaticobiliary duct. Am J Gastroenterol. 1999;94:1638–42.

    Article  PubMed  CAS  Google Scholar 

  22. Boberg KM, Schrumpf E, Bergquist A, Broome U, Pares A, Remotti H, et al. Cholangiocarcinoma in primary sclerosing cholangitis: K-ras mutations and Tp53 dysfunction are implicated in the neoplastic development. J Hepatol. 2000;32:374–80.

    Article  PubMed  CAS  Google Scholar 

  23. Kang YK, Kim WH, Lee HW, Lee HK, Kim YI. Mutation of p53 and K-ras, and loss of heterozygosity of APC in intrahepatic cholangiocarcinoma. Lab Investig. 1999;79:477–83.

    PubMed  CAS  Google Scholar 

  24. Isa T, Tomita S, Nakachi A, Miyazato H, Shimoji H, Kusano T, et al. Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma. Hepatogastroenterology. 2002;49:604–8.

    PubMed  CAS  Google Scholar 

  25. Suto T, Habano W, Sugai T, Uesugi N, Funato O, Kanno S, et al. Aberrations of the K-ras, p53, and APC genes in extrahepatic bile duct cancer. J Surg Oncol. 2000;73:158–63.

    Article  PubMed  CAS  Google Scholar 

  26. Malats N, Porta M, Pinol JL, Corominas JM, Rifa J, Real FX. Ki-ras mutations as a prognostic factor in extrahepatic bile system cancer. PANK-ras I Project Investigators. J Clin Oncol. 1995;13:1679–86.

    PubMed  CAS  Google Scholar 

  27. Tsuda H, Satarug S, Bhudhisawasdi V, Kihana T, Sugimura T, Hirohashi S. Cholangiocarcinomas in Japanese and Thai patients: difference in etiology and incidence of point mutation of the c-Ki-ras proto-oncogene. Mol Carcinog. 1992;6:266–9.

    Article  PubMed  CAS  Google Scholar 

  28. Rashid A, Ueki T, Gao YT, Houlihan PS, Wallace C, Wang BS, et al. K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res. 2002;8:3156–63.

    PubMed  CAS  Google Scholar 

  29. Deshpande V, Nduaguba A, Zimmerman SM, Kehoe SM, Macconaill LE, Lauwers GY, et al. Mutational profiling reveals PIK3CA mutations in gallbladder carcinoma. BMC Cancer. 2011;11:60.

    PubMed  Google Scholar 

  30. Tannapfel A, Sommerer F, Benicke M, Katalinic A, Uhlmann D, Witzigmann H, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut. 2003;52:706–12.

    Article  PubMed  CAS  Google Scholar 

  31. Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol. 2006;24:3069–74.

    Article  PubMed  CAS  Google Scholar 

  32. Lim HY Lee J, Chang H, Kim JS, Choi HJ, Lee MA, et al. Phase III study of gemcitabine/oxaliplatin (GEMOX) with or without erlotinib in unresectable metastatic biliary tract carcinoma. J Clin Oncol. 2011;29 (suppl; abstr LBA4032).

  33. Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP, Pitot HC, et al. 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. 2010;28:3491–7.

    Article  PubMed  CAS  Google Scholar 

  34. Sprinzl MF, Schimanski CC, Moehler M, Schadmand-Fischer S, Galle PR, Kanzler S. Gemcitabine in combination with EGF-receptor antibody (cetuximab) as a treatment of cholangiocarcinoma: a case report. BMC Cancer. 2006;6:190.

    Article  PubMed  Google Scholar 

  35. Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D, Kaczirek K, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol. 2010;11:1142–8.

    Article  PubMed  CAS  Google Scholar 

  36. Malka D FL, Mendiboure J, de la Fouchardiere C, Viret F, Asenat E, et al. A multi-center, randomized phase II trial of gemcitabine and oxaliplatin (GEMOX) alone or in combination with biweekly cetuximab in the first-line treatment of advanced biliary cancer: Interim analysis of the BINGO trial. J Clin Oncol. 2009;27 (suppl 15s; abstr 4520).

  37. Paule B, Herelle MO, Rage E, Ducreux M, Adam R, Guettier C, et al. Cetuximab plus gemcitabine-oxaliplatin (GEMOX) in patients with refractory advanced intrahepatic cholangiocarcinomas. Oncology. 2007;72:105–10.

    Article  PubMed  CAS  Google Scholar 

  38. Chang PY, Cheng MF, Lee HS, Hsieh CB, Yao NS. Preliminary experience of cetuximab in the treatment of advanced-stage biliary tract cancer. Onkologie. 2010;33:45–7.

    Article  PubMed  CAS  Google Scholar 

  39. Jensen LH, Lindebjerg J, Ploen J, Hansen T, Jakobsen AKM. Marker driven systemic treatment of inoperable cholangiocarcinomas: panitumumab and combination chemotherapy in KRAS wild-type tumors. J Clin Oncol. 2011;29 (suppl; abstr 4101).

  40. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. New Engl J Med. 2009;360:1408–17.

    Article  PubMed  Google Scholar 

  41. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29:2011–9.

    Article  PubMed  CAS  Google Scholar 

  42. Altimari A, Fiorentino M, Gabusi E, Gruppioni E, Corti B, D’Errico A, et al. Investigation of ErbB1 and ErbB2 expression for therapeutic targeting in primary liver tumours. Dig Liver Dis. 2003;35:332–8.

    Article  PubMed  CAS  Google Scholar 

  43. Wu Q, Kiguchi K, Kawamoto T, Ajiki T, Traag J, Carbajal S, et al. Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model. Cancer Res. 2007;67:3794–800.

    Article  PubMed  CAS  Google Scholar 

  44. Zhang Z, Oyesanya RA, Campbell DJ, Almenara JA, Dewitt JL, Sirica AE, et al. Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy. Hepatology. 2010;52:975–86.

    Article  PubMed  CAS  Google Scholar 

  45. Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz HJ, Yen Y, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol. 2009;64:777–83.

    Article  PubMed  CAS  Google Scholar 

  46. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.

    Article  PubMed  CAS  Google Scholar 

  47. Hida Y, Morita T, Fujita M, Miyasaka Y, Horita S, Fujioka Y, et al. Vascular endothelial growth factor expression is an independent negative predictor in extrahepatic biliary tract carcinomas. Anticancer Res. 1999;19:2257–60.

    PubMed  CAS  Google Scholar 

  48. Park BK, Paik YH, Park JY, Park KH, Bang S, Park SW, et al. The clinicopathologic significance of the expression of vascular endothelial growth factor-C in intrahepatic cholangiocarcinoma. Am J Clin Oncol. 2006;29:138–42.

    Article  PubMed  CAS  Google Scholar 

  49. Giatromanolaki A, Koukourakis MI, Simopoulos C, Polychronidis A, Sivridis E. Vascular endothelial growth factor (VEGF) expression in operable gallbladder carcinomas. Eur J Surg Oncol. 2003;29:879–83.

    Article  PubMed  CAS  Google Scholar 

  50. Giatromanolaki A, Sivridis E, Simopoulos C, Polychronidis A, Gatter KC, Harris AL, et al. Hypoxia inducible factors 1alpha and 2alpha are associated with VEGF expression and angiogenesis in gallbladder carcinomas. J Surg Oncol. 2006;94:242–7.

    Article  PubMed  CAS  Google Scholar 

  51. Zhu AX, Meyerhardt JA, Blaszkowsky LS, Kambadakone AR, Muzikansky A, Zheng H, et al. Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol. 2010;11:48–54.

    Article  PubMed  CAS  Google Scholar 

  52. Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E, Dealis C, et al. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br J Cancer. 2010;102:68–72.

    Article  PubMed  CAS  Google Scholar 

  53. El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ, Hamilton RD, et al. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Invest New Drugs [Epub ahead of print].

  54. Moehler MH, Schimanski CC, Kanzler S, Woerns S, Denzer U, Kolligs FT, et al. A randomized, double-blind, multicenter phase II AIO trial with gemcitabine plus sorafenib versus gemcitabine plus placebo in patients with chemotherapy-naive advanced or metastatic biliary tract cancer: First safety and efficacy data. J Clin Oncol. 2011;29 (suppl; abstr 4077).

    Google Scholar 

  55. Yi J, Thongprasert S, Doval D, Lee J, Cho MN, Park SH, et al. Phase II study of sunitinib as second-line treatment in advanced biliary tract carcinoma: Multicenter, multinational study. J Clin Oncol. 2011;29 (suppl; abstr e14653).

  56. Yoshikawa D, Ojima H, Kokubu A, Ochiya T, Kasai S, Hirohashi S, et al. Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. Br J Cancer. 2009;100:1257–66.

    Article  PubMed  CAS  Google Scholar 

  57. Riley E, Carloss H. Dramatic response to panitumumab and bevacizumab in metastatic gallbladder carcinoma. Oncologist. 2011;16:e1–2.

    Article  PubMed  Google Scholar 

  58. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel D, et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009;27:672–80.

    Article  PubMed  CAS  Google Scholar 

  59. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. New Engl J Med. 2009;360:563–72.

    Article  PubMed  CAS  Google Scholar 

  60. Horiuchi H, Kawamata H, Fujimori T, Kuroda Y. A MEK inhibitor (U0126) prolongs survival in nude mice bearing human gallbladder cancer cells with K-ras mutation: analysis in a novel orthotopic inoculation model. Int J Oncol. 2003;23:957–63.

    PubMed  CAS  Google Scholar 

  61. Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L, Kauh JS, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29:2357–63.

    Article  PubMed  CAS  Google Scholar 

  62. Collisson EA. An uphill battle downstream of RAF. J Clin Oncol. 2011;29:2298–300.

    Article  PubMed  Google Scholar 

  63. Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev. 2010;20:87–90.

    Article  PubMed  CAS  Google Scholar 

  64. Hansel DE, Rahman A, Hidalgo M, Thuluvath PJ, Lillemoe KD, Shulick R, et al. Identification of novel cellular targets in biliary tract cancers using global gene expression technology. Am J Pathol. 2003;163:217–29.

    Article  PubMed  CAS  Google Scholar 

  65. Kiguchi K, Carbajal S, Chan K, Beltran L, Ruffino L, Shen J, et al. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res. 2001;61:6971–6.

    PubMed  CAS  Google Scholar 

  66. Xu X, Kobayashi S, Qiao W, Li C, Xiao C, Radaeva S, et al. Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Investig. 2006;116:1843–52.

    Article  PubMed  CAS  Google Scholar 

  67. Riener MO, Bawohl M, Clavien PA, Jochum W. Rare PIK3CA hotspot mutations in carcinomas of the biliary tract. Genes Chromosom Cancer. 2008;47:363–7.

    Article  PubMed  CAS  Google Scholar 

  68. Xu RF, Sun JP, Zhang SR, Zhu GS, Li LB, Liao YL, et al. KRAS and PIK3CA but not BRAF genes are frequently mutated in Chinese cholangiocarcinoma patients. Biomed Pharmacother. 2011;65:22–6.

    Article  PubMed  CAS  Google Scholar 

  69. Hori H, Ajiki T, Mita Y, Horiuchi H, Hirata K, Matsumoto T, et al. Frequent activation of mitogen-activated protein kinase relative to Akt in extrahepatic biliary tract cancer. J Gastroenterol. 2007;42:567–72.

    Article  PubMed  CAS  Google Scholar 

  70. Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA, et al. BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation. Sci Signal. 2010;3:ra84.

    Article  PubMed  CAS  Google Scholar 

  71. Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci Signal. 2011;4:ra17.

    Article  PubMed  Google Scholar 

  72. Pai RK, Mojtahed K, Pai RK. Mutations in the RAS/RAF/MAP kinase pathway commonly occur in gallbladder adenomas but are uncommon in gallbladder adenocarcinomas. Appl Immunohistochem Mol Morphol. 2011;19:133–40.

    Article  PubMed  CAS  Google Scholar 

  73. Goldenberg D, Rosenbaum E, Argani P, Wistuba II, Sidransky D, Thuluvath PJ, et al. The V599E BRAF mutation is uncommon in biliary tract cancers. Mod Pathol. 2004;17:1386–91.

    Article  PubMed  CAS  Google Scholar 

  74. Saetta AA, Papanastasiou P, Michalopoulos NV, Gigelou F, Korkolopoulou P, Bei T, et al. Mutational analysis of BRAF in gallbladder carcinomas in association with K-ras and p53 mutations and microsatellite instability. Virchows Arch. 2004;445:179–82.

    Article  PubMed  CAS  Google Scholar 

  75. Weidner KM, Sachs M, Birchmeier W. The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells. J Cell Biol. 1993;121:145–54.

    Article  PubMed  CAS  Google Scholar 

  76. Trusolino L, Bertotti A, Comoglio PM. MET signalling: principles and functions in development, organ regeneration and cancer. Natl Rev Mol Cell Biol. 2010;11:834–48.

    Article  CAS  Google Scholar 

  77. Aishima SI, Taguchi KI, Sugimachi K, Shimada M, Sugimachi K, Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinoma. Histopathology. 2002;40:269–78.

    Article  PubMed  Google Scholar 

  78. Miyamoto M, Ojima H, Iwasaki M, Shimizu H, Kokubu A, Hiraoka N, et al. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011;105:131–8.

    Article  PubMed  CAS  Google Scholar 

  79. Terada T, Nakanuma Y, Sirica AE. Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasis. Hum Pathol. 1998;29:175–80.

    Article  PubMed  CAS  Google Scholar 

  80. Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.

    Article  PubMed  CAS  Google Scholar 

  81. Guo A, Villen J, Kornhauser J, Lee KA, Stokes MP, Rikova K, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci USA. 2008;105:692–7.

    Article  PubMed  CAS  Google Scholar 

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  1. Harvard Medical School, Tucker Gosnell Center for Gastrointestinal Cancers, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Yawkey 7E, Boston, MA, 02114, USA

    Jason E. Faris & Andrew X. Zhu

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Faris, J.E., Zhu, A.X. Targeted therapy for biliary tract cancers. J Hepatobiliary Pancreat Sci 19, 326–336 (2012). https://doi.org/10.1007/s00534-011-0496-0

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