Targeting cMET with INC280 impairs tumour growth and improves efficacy of gemcitabine in a pancreatic cancer model

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• 作者：Franziska Brandes (1)
  Katharina Schmidt (1)
  Christine Wagner (1)
  Julia Redekopf (1)
  Hans J眉rgen Schlitt (1)
  Edward Kenneth Geissler (1)
  Sven Arke Lang (1)
  
  1. Department of Surgery ; University Hospital Regensburg ; University of Regensburg ; Franz-Josef-Strauss Allee 11 ; 93053 ; Regensburg ; Germany
  
• 关键词：Pancreatic cancer ; cMET ; Resistance ; Survival
• 刊名：BMC Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：15
• 期：1
• 全文大小：1,762 KB
• 参考文献：1. Malvezzi, M, Bertuccio, P, Levi, F, Vecchia, C, Negri, E (2013) European cancer mortality predictions for the year 2013. Ann Oncol 24: pp. 792-800 CrossRef
  2. Siegel, R, Naishadham, D, Jemal, A (2013) Cancer statistics, 2013. CA Cancer J Clin 63: pp. 11-30 CrossRef
  3. Stathis, A, Moore, MJ (2010) Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7: pp. 163-72 CrossRef
  4. Conroy, T, Desseigne, F, Ychou, M, Bouche, O, Guimbaud, R, Becouarn, Y (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364: pp. 1817-25 CrossRef
  5. Bladt, F, Riethmacher, D, Isenmann, S, Aguzzi, A, Birchmeier, C (1995) Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376: pp. 768-71 CrossRef
  6. Chmielowiec, J, Borowiak, M, Morkel, M, Stradal, T, Munz, B, Werner, S (2007) c-Met is essential for wound healing in the skin. J Cell Biol 177: pp. 151-62 CrossRef
  7. Huh, CG, Factor, VM, Sanchez, A, Uchida, K, Conner, EA, Thorgeirsson, SS (2004) Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 101: pp. 4477-82 CrossRef
  8. Blumenschein, GR, Mills, GB, Gonzalez-Angulo, AM (2012) Targeting the hepatocyte growth factor-cMET axis in cancer therapy. J Clin Oncol 30: pp. 3287-96 CrossRef
  9. Gherardi, E, Birchmeier, W, Birchmeier, C, Vande Woude, G (2012) Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12: pp. 89-103 CrossRef
  10. Zhu, GH, Huang, C, Qiu, ZJ, Liu, J, Zhang, ZH, Zhao, N (2011) Expression and prognostic significance of CD151, c-Met, and integrin alpha3/alpha6 in pancreatic ductal adenocarcinoma. Dig Dis Sci 56: pp. 1090-8 CrossRef
  11. Park, JK, Kim, MA, Ryu, JK, Yoon, YB, Kim, SW, Han, HS (2012) Postoperative prognostic predictors of pancreatic ductal adenocarcinoma: clinical analysis and immunoprofile on tissue microarrays. Ann Surg Oncol 19: pp. 2664-72 CrossRef
  12. Hage, C, Rausch, V, Giese, N, Giese, T, Schonsiegel, F, Labsch, S (2013) The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer. Cell Death Dis 4: pp. e627 CrossRef
  13. Bauer, TW, Somcio, RJ, Fan, F, Liu, W, Johnson, M, Lesslie, DP (2006) Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells. Mol Cancer Ther 5: pp. 1676-82 CrossRef
  14. Hill, KS, Gaziova, I, Harrigal, L, Guerra, YA, Qiu, S, Sastry, SK (2012) Met receptor tyrosine kinase signaling induces secretion of the angiogenic chemokine interleukin-8/CXCL8 in pancreatic cancer. PLoS One 7: pp. e40420 CrossRef
  15. Liu, X, Wang, Q, Yang, G, Marando, C, Koblish, HK, Hall, LM (2011) A novel kinase inhibitor, INCB28060, blocks c-MET-dependent signaling, neoplastic activities, and cross-talk with EGFR and HER-3. Clin Cancer Res 17: pp. 7127-38 CrossRef
  16. Moser, C, Ruemmele, P, Gehmert, S, Schenk, H, Kreutz, MP, Mycielska, ME (2012) STAT5b as molecular target in pancreatic cancer鈥搃nhibition of tumor growth, angiogenesis, and metastases. Neoplasia 14: pp. 915-25
  17. Taeger, J, Moser, C, Hellerbrand, C, Mycielska, ME, Glockzin, G, Schlitt, HJ (2011) Targeting FGFR/PDGFR/VEGFR impairs tumor growth, angiogenesis, and metastasis by effects on tumor cells, endothelial cells, and pericytes in pancreatic cancer. Mol Cancer Ther 10: pp. 2157-67 CrossRef
  18. Lang, SA, Schachtschneider, P, Moser, C, Mori, A, Hackl, C, Gaumann, A (2008) Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. Mol Cancer Ther 7: pp. 3509-18 CrossRef
  19. Lang, SA, Moser, C, Gaumann, A, Klein, D, Glockzin, G, Popp, FC (2007) Targeting heat shock protein 90 in pancreatic cancer impairs insulin-like growth factor-I receptor signaling, disrupts an interleukin-6/signal-transducer and activator of transcription 3/hypoxia-inducible factor-1alpha autocrine loop, and reduces orthotopic tumor growth. Clin Cancer Res 13: pp. 6459-68 CrossRef
  20. Lang, SA, Moser, C, Fichnter-Feigl, S, Schachtschneider, P, Hellerbrand, C, Schmitz, V (2009) Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice. Hepatology 49: pp. 523-32 CrossRef
  21. Giroux, V, Malicet, C, Barthet, M, Gironella, M, Archange, C, Dagorn, JC (2006) p8 is a new target of gemcitabine in pancreatic cancer cells. Clin Cancer Res 12: pp. 235-41 CrossRef
  22. Michl, P, Gress, TM (2013) Current concepts and novel targets in advanced pancreatic cancer. Gut 62: pp. 317-26 CrossRef
  23. Lu, Z, Kleeff, J, Shrikhande, S, Zimmermann, T, Korc, M, Friess, H (2000) Expression of the multidrug-resistance 1 (MDR1) gene and prognosis in human pancreatic cancer. Pancreas 21: pp. 240-7 CrossRef
  24. Zhou, J, Liu, M, Aneja, R, Chandra, R, Lage, H, Joshi, HC (2006) Reversal of P-glycoprotein-mediated multidrug resistance in cancer cells by the c-Jun NH2-terminal kinase. Cancer Res 66: pp. 445-52 CrossRef
  25. Neesse, A, Michl, P, Frese, KK, Feig, C, Cook, N, Jacobetz, MA (2011) Stromal biology and therapy in pancreatic cancer. Gut 60: pp. 861-8 CrossRef
  26. Renzo, MF, Poulsom, R, Olivero, M, Comoglio, PM, Lemoine, NR (1995) Expression of the Met/hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 55: pp. 1129-38
  27. Paciucci, R, Vila, MR, Adell, T, Diaz, VM, Tora, M, Nakamura, T (1998) Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met. Am J Pathol 153: pp. 201-12 CrossRef
  28. Avan, A, Caretti, V, Funel, N, Galvani, E, Maftouh, M, Honeywell, RJ (2013) Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma. Cancer Res 73: pp. 6745-56 CrossRef
  29. Christensen, JG, Schreck, R, Burrows, J, Kuruganti, P, Chan, E, Le, P (2003) A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. Cancer Res 63: pp. 7345-55
  30. Jin, H, Yang, R, Zheng, Z, Romero, M, Ross, J, Bou-Reslan, H (2008) MetMAb, the one-armed 5D5 anti-c-Met antibody, inhibits orthotopic pancreatic tumor growth and improves survival. Cancer Res 68: pp. 4360-8 CrossRef
  31. Ucar, DA, Magis, AT, He, DH, Lawrence, NJ, Sebti, SM, Kurenova, E (2013) Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo. Anticancer Agents Med Chem 13: pp. 595-602 CrossRef
  32. Ide, T, Kitajima, Y, Miyoshi, A, Ohtsuka, T, Mitsuno, M, Ohtaka, K (2007) The hypoxic environment in tumor-stromal cells accelerates pancreatic cancer progression via the activation of paracrine hepatocyte growth factor/c-Met signaling. Ann Surg Oncol 14: pp. 2600-7 CrossRef
  33. Ying, JE, Zhu, LM, Liu, BX (2012) Developments in metastatic pancreatic cancer: is gemcitabine still the standard?. World J Gastroenterol 18: pp. 736-45 CrossRef
  34. Shah, AN, Summy, JM, Zhang, J, Park, SI, Parikh, NU, Gallick, GE (2007) Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann Surg Oncol 14: pp. 3629-37 CrossRef
  35. Li, C, Wu, JJ, Hynes, M, Dosch, J, Sarkar, B, Welling, TH (2011) c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 141: pp. 2218-27 CrossRef
  36. Bentires-Alj, M, Barbu, V, Fillet, M, Chariot, A, Relic, B, Jacobs, N (2003) NF-kappaB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene 22: pp. 90-7 CrossRef
  37. Zhang, W, Chen, H, Liu, DL, Li, H, Luo, J, Zhang, JH (2013) Emodin sensitizes the gemcitabine-resistant cell line Bxpc-3/Gem to gemcitabine via downregulation of NF-kappaB and its regulated targets. Int J Oncol 42: pp. 1189-96
  38. Doublier, S, Belisario, DC, Polimeni, M, Annaratone, L, Riganti, C, Allia, E (2012) HIF-1 activation induces doxorubicin resistance in MCF7 3-D spheroids via P-glycoprotein expression: a potential model of the chemo-resistance of invasive micropapillary carcinoma of the breast. BMC Cancer 12: pp. 4 CrossRef
  39. Matsumura, A, Kubota, T, Taiyoh, H, Fujiwara, H, Okamoto, K, Ichikawa, D (2013) HGF regulates VEGF expression via the c-Met receptor downstream pathways, PI3K/Akt, MAPK and STAT3, in CT26 murine cells. Int J Oncol 42: pp. 535-42
  40. Ding, Y, Cravero, JD, Adrian, K, Grippo, P (2010) Modeling pancreatic cancer in vivo: from xenograft and carcinogen-induced systems to genetically engineered mice. Pancreas 39: pp. 283-92 CrossRef
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

Background Expression and activation of the cMET receptor have been implicated in tumor progression and resistance to chemotherapy in human pancreatic cancer. In this regard we assessed the effects of targeting cMET in pancreatic cancer models in vitro and in vivo. Methods Human (L3.6pl, BxP3, HPAF-II, MiaPaCa2) and murine (Panc02) pancreatic cancer cell lines, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) were used for the experiments. Furthermore, the human pancreatic cancer cell line MiaPaCa2 with acquired resistance to gemcitabine was employed (MiaPaCa2(G250)). For targeting the cMET receptor, the oral available, ATP-competitive inhibitor INC280 was used. Effects of cMET inhibition on cancer and stromal cells were determined by growth assays, western blotting, motility assays and ELISA. Moreover, orthotopic xenogeneic and syngeneic mouse (BALB-C nu/nu; C57BL/6) models were used to assess in vivo efficacy of targeting cMET alone and in combination with gemcitabine. Results Treatment with INC280 impairs activation of signaling intermediates in pancreatic cancer cells and ECs, particularly when cells were stimulated with hepatocyte growth factor (HGF). Moreover, motility of cancer cells and ECs in response to HGF was reduced upon treatment with INC280. Only minor effects on VSMCs were detected. Interestingly, MiaPaCa2(G250) showed an increase in cMET expression and cMET inhibition abrogated HGF-induced effects on growth, motility and signaling as well as DFX-hypoxia HIF-1alpha and MDR-1 expression in vitro. In vivo, therapy with INC280 alone led to inhibition of orthotopic tumor growth in xenogeneic and syngeneic models. Similar to in vitro results, cMET expression was increased upon treatment with gemcitabine, and combination of the cMET inhibitor with gemcitabine improved anti-neoplastic capacity in an orthotopic syngeneic model. Immunohistochemical analysis revealed a significant inhibition of tumor cell proliferation (Ki67) and tumor vascularization (CD31). Finally, combination of gemcitabine with INC280 significantly prolonged survival in the orthotopic syngeneic tumor model even when treatment with the cMET inhibitor was initiated at an advanced stage of disease. Conclusions These data provide evidence that targeting cMET in combination with gemcitabine may be effective in human pancreatic cancer and warrants further clinical evaluation.