Skip to main content
Erschienen in: Cancer and Metastasis Reviews 1-2/2013

01.06.2013 | NON-THEMATIC REVIEW

Targeting the Ras–ERK pathway in pancreatic adenocarcinoma

verfasst von: Cindy Neuzillet, Pascal Hammel, Annemilaï Tijeras-Raballand, Anne Couvelard, Eric Raymond

Erschienen in: Cancer and Metastasis Reviews | Ausgabe 1-2/2013

Einloggen, um Zugang zu erhalten

Abstract

Pancreatic ductal adenocarcinoma (PAC) stands as the poorest prognostic tumor of the digestive tract with limited therapeutic options. PAC carcinogenesis is associated with the loss of function of tumor suppressor genes such as INK4A, TP53, BRCA2, and DPC4, and only a few activated oncogenes among which K-RAS mutations are the most prevalent. The K-RAS mutation occurs early in PAC carcinogenesis, driving downstream activation of MEK and ERK1/2 which promote survival, invasion, and migration of cancer cells. In PAC models, inhibition of members of the Ras–ERK pathway blocks cellular proliferation and metastasis development. As oncogenic Ras does not appear to be a suitable drug target, inhibitors targeting downstream kinases including Raf and MEK have been developed and are currently under evaluation in clinical trials. In this review, we describe the role of the Ras–ERK pathway in pancreatic carcinogenesis and as a new therapeutic target for the treatment of PAC.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
2.
Zurück zum Zitat Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. doi:10.1002/ijc.25516. Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer. doi:10.​1002/​ijc.​25516.
5.
Zurück zum Zitat Burris, H. A., 3rd, Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M. R., et al. (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology, 15(6), 2403–2413.PubMed Burris, H. A., 3rd, Moore, M. J., Andersen, J., Green, M. R., Rothenberg, M. L., Modiano, M. R., et al. (1997). Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. Journal of Clinical Oncology, 15(6), 2403–2413.PubMed
6.
Zurück zum Zitat Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., et al. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25(15), 1960–1966. doi:10.1200/JCO.2006.07.9525.PubMedCrossRef Moore, M. J., Goldstein, D., Hamm, J., Figer, A., Hecht, J. R., Gallinger, S., et al. (2007). Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology, 25(15), 1960–1966. doi:10.​1200/​JCO.​2006.​07.​9525.PubMedCrossRef
7.
Zurück zum Zitat Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., et al. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England Journal of Medicine, 364(19), 1817–1825. doi:10.1056/NEJMoa1011923.PubMedCrossRef Conroy, T., Desseigne, F., Ychou, M., Bouche, O., Guimbaud, R., Becouarn, Y., et al. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. The New England Journal of Medicine, 364(19), 1817–1825. doi:10.​1056/​NEJMoa1011923.PubMedCrossRef
8.
Zurück zum Zitat McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W., Chang, F., et al. (2007). Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochimica et Biophysica Acta, 1773(8), 1263–1284. doi:10.1016/j.bbamcr.2006.10.001.PubMedCrossRef McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Wong, E. W., Chang, F., et al. (2007). Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochimica et Biophysica Acta, 1773(8), 1263–1284. doi:10.​1016/​j.​bbamcr.​2006.​10.​001.PubMedCrossRef
9.
Zurück zum Zitat Preis, M., & Korc, M. (2010). Kinase signaling pathways as targets for intervention in pancreatic cancer. Cancer Biology & Therapy, 9(10), 754–763.CrossRef Preis, M., & Korc, M. (2010). Kinase signaling pathways as targets for intervention in pancreatic cancer. Cancer Biology & Therapy, 9(10), 754–763.CrossRef
11.
Zurück zum Zitat Chappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., et al. (2011). Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget, 2(3), 135–164.PubMed Chappell, W. H., Steelman, L. S., Long, J. M., Kempf, R. C., Abrams, S. L., Franklin, R. A., et al. (2011). Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health. Oncotarget, 2(3), 135–164.PubMed
13.
Zurück zum Zitat Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., et al. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468(7326), 968–972. doi:10.1038/nature09627.PubMedCrossRef Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., et al. (2010). COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature, 468(7326), 968–972. doi:10.​1038/​nature09627.PubMedCrossRef
17.
23.
Zurück zum Zitat Wang, S., Ghosh, R. N., & Chellappan, S. P. (1998). Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Molecular and Cellular Biology, 18(12), 7487–7498.PubMed Wang, S., Ghosh, R. N., & Chellappan, S. P. (1998). Raf-1 physically interacts with Rb and regulates its function: a link between mitogenic signaling and cell cycle regulation. Molecular and Cellular Biology, 18(12), 7487–7498.PubMed
24.
Zurück zum Zitat Ballif, B. A., & Blenis, J. (2001). Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth & Differentiation, 12(8), 397–408. Ballif, B. A., & Blenis, J. (2001). Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth & Differentiation, 12(8), 397–408.
26.
Zurück zum Zitat Allan, L. A., Morrice, N., Brady, S., Magee, G., Pathak, S., & Clarke, P. R. (2003). Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nature Cell Biology, 5(7), 647–654. doi:10.1038/ncb1005 ncb1005.PubMedCrossRef Allan, L. A., Morrice, N., Brady, S., Magee, G., Pathak, S., & Clarke, P. R. (2003). Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK. Nature Cell Biology, 5(7), 647–654. doi:10.​1038/​ncb1005 ncb1005.PubMedCrossRef
27.
Zurück zum Zitat Sahu, R. P., Batra, S., Kandala, P. K., Brown, T. L., & Srivastava, S. K. (2011). The role of K-ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines. Cancer Chemotherapy and Pharmacology, 67(2), 481–487. doi:10.1007/s00280-010-1463-1.PubMedCrossRef Sahu, R. P., Batra, S., Kandala, P. K., Brown, T. L., & Srivastava, S. K. (2011). The role of K-ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines. Cancer Chemotherapy and Pharmacology, 67(2), 481–487. doi:10.​1007/​s00280-010-1463-1.PubMedCrossRef
28.
Zurück zum Zitat Maida, Y., Kyo, S., Kanaya, T., Wang, Z., Yatabe, N., Tanaka, M., et al. (2002). Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene, 21(26), 4071–4079. doi:10.1038/sj.onc.1205509.PubMedCrossRef Maida, Y., Kyo, S., Kanaya, T., Wang, Z., Yatabe, N., Tanaka, M., et al. (2002). Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene, 21(26), 4071–4079. doi:10.​1038/​sj.​onc.​1205509.PubMedCrossRef
29.
Zurück zum Zitat Ellenrieder, V., Hendler, S. F., Boeck, W., Seufferlein, T., Menke, A., Ruhland, C., et al. (2001). Transforming growth factor beta1 treatment leads to an epithelial–mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Research, 61(10), 4222–4228.PubMed Ellenrieder, V., Hendler, S. F., Boeck, W., Seufferlein, T., Menke, A., Ruhland, C., et al. (2001). Transforming growth factor beta1 treatment leads to an epithelial–mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Research, 61(10), 4222–4228.PubMed
30.
32.
Zurück zum Zitat Lim, J. H., Lee, E. S., You, H. J., Lee, J. W., Park, J. W., & Chun, Y. S. (2004). Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion. Oncogene, 23(58), 9427–9431. doi:10.1038/sj.onc.1208003.PubMedCrossRef Lim, J. H., Lee, E. S., You, H. J., Lee, J. W., Park, J. W., & Chun, Y. S. (2004). Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: a novel mechanism of Ras-mediated tumor promotion. Oncogene, 23(58), 9427–9431. doi:10.​1038/​sj.​onc.​1208003.PubMedCrossRef
34.
35.
Zurück zum Zitat Lee, J., Jang, K. T., Ki, C. S., Lim, T., Park, Y. S., Lim, H. Y., et al. (2007). Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer, 109(8), 1561–1569. doi:10.1002/cncr.22559.PubMedCrossRef Lee, J., Jang, K. T., Ki, C. S., Lim, T., Park, Y. S., Lim, H. Y., et al. (2007). Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma. Cancer, 109(8), 1561–1569. doi:10.​1002/​cncr.​22559.PubMedCrossRef
36.
Zurück zum Zitat Luo, G., Long, J., Qiu, L., Liu, C., Xu, J., & Yu, X. (2011). Role of epidermal growth factor receptor expression on patient survival in pancreatic cancer: a meta-analysis. Pancreatology, 11(6), 595–600. doi:10.1159/000334465.PubMedCrossRef Luo, G., Long, J., Qiu, L., Liu, C., Xu, J., & Yu, X. (2011). Role of epidermal growth factor receptor expression on patient survival in pancreatic cancer: a meta-analysis. Pancreatology, 11(6), 595–600. doi:10.​1159/​000334465.PubMedCrossRef
37.
Zurück zum Zitat Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N., & Depinho, R. A. (2006). Genetics and biology of pancreatic ductal adenocarcinoma. Genes & Development, 20(10), 1218–1249. doi:10.1101/gad.1415606.CrossRef Hezel, A. F., Kimmelman, A. C., Stanger, B. Z., Bardeesy, N., & Depinho, R. A. (2006). Genetics and biology of pancreatic ductal adenocarcinoma. Genes & Development, 20(10), 1218–1249. doi:10.​1101/​gad.​1415606.CrossRef
39.
Zurück zum Zitat Morris, J. P. T., Wang, S. C., & Hebrok, M. (2010). KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nature Reviews. Cancer, 10(10), 683–695. doi:10.1038/nrc2899.PubMedCrossRef Morris, J. P. T., Wang, S. C., & Hebrok, M. (2010). KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nature Reviews. Cancer, 10(10), 683–695. doi:10.​1038/​nrc2899.PubMedCrossRef
40.
42.
Zurück zum Zitat Matthaios, D., Zarogoulidis, P., Balgouranidou, I., Chatzaki, E., & Kakolyris, S. (2011). Molecular pathogenesis of pancreatic cancer and clinical perspectives. Oncology, 81(3–4), 259–272. doi:10.1159/000334449.PubMedCrossRef Matthaios, D., Zarogoulidis, P., Balgouranidou, I., Chatzaki, E., & Kakolyris, S. (2011). Molecular pathogenesis of pancreatic cancer and clinical perspectives. Oncology, 81(3–4), 259–272. doi:10.​1159/​000334449.PubMedCrossRef
44.
Zurück zum Zitat Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321(5897), 1801–1806. doi:10.1126/science.1164368.PubMedCrossRef Jones, S., Zhang, X., Parsons, D. W., Lin, J. C., Leary, R. J., Angenendt, P., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science, 321(5897), 1801–1806. doi:10.​1126/​science.​1164368.PubMedCrossRef
45.
Zurück zum Zitat Mazur, P. K., & Siveke, J. T. (2011). Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology. Gut. doi:10.1136/gutjnl-2011-300756. Mazur, P. K., & Siveke, J. T. (2011). Genetically engineered mouse models of pancreatic cancer: unravelling tumour biology and progressing translational oncology. Gut. doi:10.​1136/​gutjnl-2011-300756.
46.
Zurück zum Zitat Skoulidis, F., Cassidy, L. D., Pisupati, V., Jonasson, J. G., Bjarnason, H., Eyfjord, J. E., et al. (2010). Germline Brca2 heterozygosity promotes Kras(G12D)-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell, 18(5), 499–509. doi:10.1016/j.ccr.2010.10.015.PubMedCrossRef Skoulidis, F., Cassidy, L. D., Pisupati, V., Jonasson, J. G., Bjarnason, H., Eyfjord, J. E., et al. (2010). Germline Brca2 heterozygosity promotes Kras(G12D)-driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell, 18(5), 499–509. doi:10.​1016/​j.​ccr.​2010.​10.​015.PubMedCrossRef
48.
Zurück zum Zitat Zhao, S., Venkatasubbarao, K., Lazor, J. W., Sperry, J., Jin, C., Cao, L., et al. (2008). Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Research, 68(11), 4221–4228. doi:10.1158/0008-5472.CAN-07-5123.PubMedCrossRef Zhao, S., Venkatasubbarao, K., Lazor, J. W., Sperry, J., Jin, C., Cao, L., et al. (2008). Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Research, 68(11), 4221–4228. doi:10.​1158/​0008-5472.​CAN-07-5123.PubMedCrossRef
49.
Zurück zum Zitat Bachet, J. B., Marechal, R., Demetter, P., Bonnetain, F., Couvelard, A., Svrcek, M., et al. (2012). Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Annals of Oncology. doi:10.1093/annonc/mdr617. Bachet, J. B., Marechal, R., Demetter, P., Bonnetain, F., Couvelard, A., Svrcek, M., et al. (2012). Contribution of CXCR4 and SMAD4 in predicting disease progression pattern and benefit from adjuvant chemotherapy in resected pancreatic adenocarcinoma. Annals of Oncology. doi:10.​1093/​annonc/​mdr617.
50.
52.
Zurück zum Zitat Handra-Luca, A., Lesty, C., Hammel, P., Sauvanet, A., Rebours, V., Martin, A., et al. (2012). Biological and prognostic relevance of mitogen-activated protein kinases in pancreatic adenocarcinoma. Pancreas, 41(3), 416–421. doi:10.1097/MPA.0b013e318238379d.PubMedCrossRef Handra-Luca, A., Lesty, C., Hammel, P., Sauvanet, A., Rebours, V., Martin, A., et al. (2012). Biological and prognostic relevance of mitogen-activated protein kinases in pancreatic adenocarcinoma. Pancreas, 41(3), 416–421. doi:10.​1097/​MPA.​0b013e318238379d​.PubMedCrossRef
54.
Zurück zum Zitat Duner, S., Lopatko Lindman, J., Ansari, D., Gundewar, C., & Andersson, R. (2010). Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology, 10(6), 673–681. doi:10.1159/000320711.PubMedCrossRef Duner, S., Lopatko Lindman, J., Ansari, D., Gundewar, C., & Andersson, R. (2010). Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. Pancreatology, 10(6), 673–681. doi:10.​1159/​000320711.PubMedCrossRef
56.
Zurück zum Zitat Vasseur, S. T. R., Tournaire, R., & Iovanna, J. L. (2010). Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers, 2(4), 2138–2152. doi:10.3390/cancers2042138.CrossRef Vasseur, S. T. R., Tournaire, R., & Iovanna, J. L. (2010). Hypoxia induced tumor metabolic switch contributes to pancreatic cancer aggressiveness. Cancers, 2(4), 2138–2152. doi:10.​3390/​cancers2042138.CrossRef
58.
Zurück zum Zitat Xiong, H. Q., Rosenberg, A., LoBuglio, A., Schmidt, W., Wolff, R. A., Deutsch, J., et al. (2004). Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. Journal of Clinical Oncology, 22(13), 2610–2616. doi:10.1200/JCO.2004.12.040 22/13/2610.PubMedCrossRef Xiong, H. Q., Rosenberg, A., LoBuglio, A., Schmidt, W., Wolff, R. A., Deutsch, J., et al. (2004). Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. Journal of Clinical Oncology, 22(13), 2610–2616. doi:10.​1200/​JCO.​2004.​12.​040 22/​13/​2610.PubMedCrossRef
59.
Zurück zum Zitat Philip, P. A., Benedetti, J., Corless, C. L., Wong, R., O’Reilly, E. M., Flynn, P. J., et al. (2010). Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. Journal of Clinical Oncology, 28(22), 3605–3610. doi:10.1200/JCO.2009.25.7550.PubMedCrossRef Philip, P. A., Benedetti, J., Corless, C. L., Wong, R., O’Reilly, E. M., Flynn, P. J., et al. (2010). Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. Journal of Clinical Oncology, 28(22), 3605–3610. doi:10.​1200/​JCO.​2009.​25.​7550.PubMedCrossRef
60.
Zurück zum Zitat Van Cutsem, E., Vervenne, W. L., Bennouna, J., Humblet, Y., Gill, S., Van Laethem, J. L., et al. (2009). Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. Journal of Clinical Oncology, 27(13), 2231–2237. doi:10.1200/JCO.2008.20.0238.PubMedCrossRef Van Cutsem, E., Vervenne, W. L., Bennouna, J., Humblet, Y., Gill, S., Van Laethem, J. L., et al. (2009). Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. Journal of Clinical Oncology, 27(13), 2231–2237. doi:10.​1200/​JCO.​2008.​20.​0238.PubMedCrossRef
61.
Zurück zum Zitat Graeven, U., Kremer, B., Sudhoff, T., Killing, B., Rojo, F., Weber, D., et al. (2006). Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. British Journal of Cancer, 94(9), 1293–1299. doi:10.1038/sj.bjc.6603083.PubMedCrossRef Graeven, U., Kremer, B., Sudhoff, T., Killing, B., Rojo, F., Weber, D., et al. (2006). Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer. British Journal of Cancer, 94(9), 1293–1299. doi:10.​1038/​sj.​bjc.​6603083.PubMedCrossRef
62.
Zurück zum Zitat Safran, H., Iannitti, D., Ramanathan, R., Schwartz, J. D., Steinhoff, M., Nauman, C., et al. (2004). Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Investigation, 22(5), 706–712.PubMedCrossRef Safran, H., Iannitti, D., Ramanathan, R., Schwartz, J. D., Steinhoff, M., Nauman, C., et al. (2004). Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Investigation, 22(5), 706–712.PubMedCrossRef
63.
Zurück zum Zitat Fountzilas, G., Bobos, M., Kalogera-Fountzila, A., Xiros, N., Murray, S., Linardou, H., et al. (2008). Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Investigation, 26(8), 784–793. doi:10.1080/07357900801918611.PubMedCrossRef Fountzilas, G., Bobos, M., Kalogera-Fountzila, A., Xiros, N., Murray, S., Linardou, H., et al. (2008). Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II Study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Investigation, 26(8), 784–793. doi:10.​1080/​0735790080191861​1.PubMedCrossRef
64.
Zurück zum Zitat Ignatiadis, M., Polyzos, A., Stathopoulos, G. P., Tselepatiotis, E., Christophylakis, C., Kalbakis, K., et al. (2006). A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology, 71(3–4), 159–163. doi:10.1159/000106064.PubMedCrossRef Ignatiadis, M., Polyzos, A., Stathopoulos, G. P., Tselepatiotis, E., Christophylakis, C., Kalbakis, K., et al. (2006). A multicenter phase II study of docetaxel in combination with gefitinib in gemcitabine-pretreated patients with advanced/metastatic pancreatic cancer. Oncology, 71(3–4), 159–163. doi:10.​1159/​000106064.PubMedCrossRef
65.
Zurück zum Zitat Brell, J. M., Matin, K., Evans, T., Volkin, R. L., Kiefer, G. J., Schlesselman, J. J., et al. (2009). Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology, 76(4), 270–274. doi:10.1159/000206141.PubMedCrossRef Brell, J. M., Matin, K., Evans, T., Volkin, R. L., Kiefer, G. J., Schlesselman, J. J., et al. (2009). Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology, 76(4), 270–274. doi:10.​1159/​000206141.PubMedCrossRef
66.
Zurück zum Zitat Safran, H. M. T., Bahary, N., Whiting, S., Lopez, C. D., Sun, W., Charpentier, K., Shipley, J., Anderson, E., McNulty, B., Schumacher, A., Clark, A., Vakharia, J., Kennedy, T., & Sio, T. (2011). Lapatinib and gemcitabine for metastatic pancreatic cancer: a phase II study. American Journal of Clinical Oncology, 34(1), 50–52. doi:10.1097/COC.0b013e3181d26b01.CrossRef Safran, H. M. T., Bahary, N., Whiting, S., Lopez, C. D., Sun, W., Charpentier, K., Shipley, J., Anderson, E., McNulty, B., Schumacher, A., Clark, A., Vakharia, J., Kennedy, T., & Sio, T. (2011). Lapatinib and gemcitabine for metastatic pancreatic cancer: a phase II study. American Journal of Clinical Oncology, 34(1), 50–52. doi:10.​1097/​COC.​0b013e3181d26b01​.CrossRef
68.
Zurück zum Zitat Martin, N. E., Brunner, T. B., Kiel, K. D., DeLaney, T. F., Regine, W. F., Mohiuddin, M., et al. (2004). A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clinical Cancer Research, 10(16), 5447–5454. doi:10.1158/1078-0432.CCR-04-024810/16/5447.PubMedCrossRef Martin, N. E., Brunner, T. B., Kiel, K. D., DeLaney, T. F., Regine, W. F., Mohiuddin, M., et al. (2004). A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer. Clinical Cancer Research, 10(16), 5447–5454. doi:10.​1158/​1078-0432.​CCR-04-024810/​16/​5447.PubMedCrossRef
69.
Zurück zum Zitat Toubaji, A., Achtar, M., Provenzano, M., Herrin, V. E., Behrens, R., Hamilton, M., et al. (2008). Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunology, Immunotherapy, 57(9), 1413–1420. doi:10.1007/s00262-008-0477-6.PubMedCrossRef Toubaji, A., Achtar, M., Provenzano, M., Herrin, V. E., Behrens, R., Hamilton, M., et al. (2008). Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunology, Immunotherapy, 57(9), 1413–1420. doi:10.​1007/​s00262-008-0477-6.PubMedCrossRef
70.
Zurück zum Zitat Alberts, S. R., Schroeder, M., Erlichman, C., Steen, P. D., Foster, N. R., Moore, D. F., Jr., et al. (2004). Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. Journal of Clinical Oncology, 22(24), 4944–4950. doi:10.1200/JCO.2004.05.034.PubMedCrossRef Alberts, S. R., Schroeder, M., Erlichman, C., Steen, P. D., Foster, N. R., Moore, D. F., Jr., et al. (2004). Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. Journal of Clinical Oncology, 22(24), 4944–4950. doi:10.​1200/​JCO.​2004.​05.​034.PubMedCrossRef
72.
Zurück zum Zitat Kindler, H. L., Wroblewski, K., Wallace, J. A., Hall, M. J., Locker, G., Nattam, S., et al. (2012). Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Investigational New Drugs, 30(1), 382–386. doi:10.1007/s10637-010-9526-z.PubMedCrossRef Kindler, H. L., Wroblewski, K., Wallace, J. A., Hall, M. J., Locker, G., Nattam, S., et al. (2012). Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. Investigational New Drugs, 30(1), 382–386. doi:10.​1007/​s10637-010-9526-z.PubMedCrossRef
73.
Zurück zum Zitat El-Khoueiry, A. B., Ramanathan, R. K., Yang, D. Y., Zhang, W., Shibata, S., Wright, J. J., et al. (2012). A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Investigational New Drugs, 30(3), 1175–1183. doi:10.1007/s10637-011-9658-9.PubMedCrossRef El-Khoueiry, A. B., Ramanathan, R. K., Yang, D. Y., Zhang, W., Shibata, S., Wright, J. J., et al. (2012). A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer. Investigational New Drugs, 30(3), 1175–1183. doi:10.​1007/​s10637-011-9658-9.PubMedCrossRef
74.
Zurück zum Zitat Lang, S. A., Schachtschneider, P., Moser, C., Mori, A., Hackl, C., Gaumann, A., et al. (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. Molecular Cancer Therapeutics, 7(11), 3509–3518. doi:10.1158/1535-7163.MCT-08-0373.PubMedCrossRef Lang, S. A., Schachtschneider, P., Moser, C., Mori, A., Hackl, C., Gaumann, A., et al. (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. Molecular Cancer Therapeutics, 7(11), 3509–3518. doi:10.​1158/​1535-7163.​MCT-08-0373.PubMedCrossRef
75.
78.
Zurück zum Zitat Lorusso, P. M., Adjei, A. A., Varterasian, M., Gadgeel, S., Reid, J., Mitchell, D. Y., et al. (2005). Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. Journal of Clinical Oncology, 23(23), 5281–5293. doi:10.1200/JCO.2005.14.415.PubMedCrossRef Lorusso, P. M., Adjei, A. A., Varterasian, M., Gadgeel, S., Reid, J., Mitchell, D. Y., et al. (2005). Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. Journal of Clinical Oncology, 23(23), 5281–5293. doi:10.​1200/​JCO.​2005.​14.​415.PubMedCrossRef
79.
Zurück zum Zitat Rinehart, J., Adjei, A. A., Lorusso, P. M., Waterhouse, D., Hecht, J. R., Natale, R. B., et al. (2004). Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. Journal of Clinical Oncology, 22(22), 4456–4462. doi:10.1200/JCO.2004.01.185.PubMedCrossRef Rinehart, J., Adjei, A. A., Lorusso, P. M., Waterhouse, D., Hecht, J. R., Natale, R. B., et al. (2004). Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. Journal of Clinical Oncology, 22(22), 4456–4462. doi:10.​1200/​JCO.​2004.​01.​185.PubMedCrossRef
80.
Zurück zum Zitat LoRusso, P. M., Krishnamurthi, S. S., Rinehart, J. J., Nabell, L. M., Malburg, L., Chapman, P. B., et al. (2010). Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clinical Cancer Research, 16(6), 1924–1937. doi:10.1158/1078-0432.CCR-09-1883.PubMedCrossRef LoRusso, P. M., Krishnamurthi, S. S., Rinehart, J. J., Nabell, L. M., Malburg, L., Chapman, P. B., et al. (2010). Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clinical Cancer Research, 16(6), 1924–1937. doi:10.​1158/​1078-0432.​CCR-09-1883.PubMedCrossRef
82.
Zurück zum Zitat Huang, W., Yang, A. H., Matsumoto, D., Collette, W., Marroquin, L., Ko, M., et al. (2009). PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. Journal of Ocular Pharmacology and Therapeutics, 25(6), 519–530. doi:10.1089/jop. 2009.0060.PubMedCrossRef Huang, W., Yang, A. H., Matsumoto, D., Collette, W., Marroquin, L., Ko, M., et al. (2009). PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. Journal of Ocular Pharmacology and Therapeutics, 25(6), 519–530. doi:10.​1089/​jop.​ 2009.​0060.PubMedCrossRef
83.
Zurück zum Zitat Faivre, S., Ronot, M., Dreyer, C., Serrate, C., Hentic, O., Bouattour, M., et al. (2012). Imaging response in neuroendocrine tumors treated with targeted therapies: the experience of sunitinib. Targeted Oncology, 7(2), 127–133. doi:10.1007/s11523-012-0216-y.PubMedCrossRef Faivre, S., Ronot, M., Dreyer, C., Serrate, C., Hentic, O., Bouattour, M., et al. (2012). Imaging response in neuroendocrine tumors treated with targeted therapies: the experience of sunitinib. Targeted Oncology, 7(2), 127–133. doi:10.​1007/​s11523-012-0216-y.PubMedCrossRef
85.
Zurück zum Zitat Diep, C. H., Munoz, R. M., Choudhary, A., Von Hoff, D. D., & Han, H. (2011). Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells. Clinical Cancer Research, 17(9), 2744–2756. doi:10.1158/1078-0432.CCR-10-2214.PubMedCrossRef Diep, C. H., Munoz, R. M., Choudhary, A., Von Hoff, D. D., & Han, H. (2011). Synergistic effect between erlotinib and MEK inhibitors in KRAS wild-type human pancreatic cancer cells. Clinical Cancer Research, 17(9), 2744–2756. doi:10.​1158/​1078-0432.​CCR-10-2214.PubMedCrossRef
86.
Zurück zum Zitat Wang, H., Daouti, S., Li, W. H., Wen, Y., Rizzo, C., Higgins, B., et al. (2011). Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Research, 71(16), 5535–5545. doi:10.1158/0008-5472.CAN-10-4351.PubMedCrossRef Wang, H., Daouti, S., Li, W. H., Wen, Y., Rizzo, C., Higgins, B., et al. (2011). Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation. Cancer Research, 71(16), 5535–5545. doi:10.​1158/​0008-5472.​CAN-10-4351.PubMedCrossRef
87.
Zurück zum Zitat Little, A. S., Balmanno, K., Sale, M. J., Smith, P. D., & Cook, S. J. (2012). Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochemical Society Transactions, 40(1), 73–78. doi:10.1042/BST20110647.PubMedCrossRef Little, A. S., Balmanno, K., Sale, M. J., Smith, P. D., & Cook, S. J. (2012). Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochemical Society Transactions, 40(1), 73–78. doi:10.​1042/​BST20110647.PubMedCrossRef
88.
Zurück zum Zitat Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., et al. (2006). BRAF mutation predicts sensitivity to MEK inhibition. Nature, 439(7074), 358–362. doi:10.1038/nature04304.PubMedCrossRef Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G., Basso, A., et al. (2006). BRAF mutation predicts sensitivity to MEK inhibition. Nature, 439(7074), 358–362. doi:10.​1038/​nature04304.PubMedCrossRef
89.
91.
Zurück zum Zitat Yeh, J. J., Routh, E. D., Rubinas, T., Peacock, J., Martin, T. D., Shen, X. J., et al. (2009). KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Molecular Cancer Therapeutics, 8(4), 834–843. doi:10.1158/1535-7163.MCT-08-0972.PubMedCrossRef Yeh, J. J., Routh, E. D., Rubinas, T., Peacock, J., Martin, T. D., Shen, X. J., et al. (2009). KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer. Molecular Cancer Therapeutics, 8(4), 834–843. doi:10.​1158/​1535-7163.​MCT-08-0972.PubMedCrossRef
92.
Zurück zum Zitat Loboda, A., Nebozhyn, M., Klinghoffer, R., Frazier, J., Chastain, M., Arthur, W., et al. (2010). A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Medical Genomics, 3, 26. doi:10.1186/1755-8794-3-26.PubMedCrossRef Loboda, A., Nebozhyn, M., Klinghoffer, R., Frazier, J., Chastain, M., Arthur, W., et al. (2010). A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Medical Genomics, 3, 26. doi:10.​1186/​1755-8794-3-26.PubMedCrossRef
93.
Zurück zum Zitat Holt, S. V., Logie, A., Odedra, R., Heier, A., Heaton, S. P., Alferez, D., et al. (2012). The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. British Journal of Cancer, 106(5), 858–866. doi:10.1038/bjc.2012.8 bjc20128.PubMedCrossRef Holt, S. V., Logie, A., Odedra, R., Heier, A., Heaton, S. P., Alferez, D., et al. (2012). The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models. British Journal of Cancer, 106(5), 858–866. doi:10.​1038/​bjc.​2012.​8 bjc20128.PubMedCrossRef
94.
Zurück zum Zitat Urick, M. E., Chung, E. J., Shield, W. P., 3rd, Gerber, N., White, A., Sowers, A., et al. (2011). Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. Clinical Cancer Research, 17(15), 5038–5047. doi:10.1158/1078-0432.CCR-11-0358.PubMedCrossRef Urick, M. E., Chung, E. J., Shield, W. P., 3rd, Gerber, N., White, A., Sowers, A., et al. (2011). Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition. Clinical Cancer Research, 17(15), 5038–5047. doi:10.​1158/​1078-0432.​CCR-11-0358.PubMedCrossRef
95.
97.
Zurück zum Zitat Halilovic, E., She, Q. B., Ye, Q., Pagliarini, R., Sellers, W. R., Solit, D. B., et al. (2010). PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Research, 70(17), 6804–6814. doi:10.1158/0008-5472.CAN-10-0409.PubMedCrossRef Halilovic, E., She, Q. B., Ye, Q., Pagliarini, R., Sellers, W. R., Solit, D. B., et al. (2010). PIK3CA mutation uncouples tumor growth and cyclin D1 regulation from MEK/ERK and mutant KRAS signaling. Cancer Research, 70(17), 6804–6814. doi:10.​1158/​0008-5472.​CAN-10-0409.PubMedCrossRef
98.
Zurück zum Zitat Chang, Q., Chen, E., & Hedley, D. W. (2009). Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models. Cancer Biology & Therapy, 8(20), 1893–1901.CrossRef Chang, Q., Chen, E., & Hedley, D. W. (2009). Effects of combined inhibition of MEK and mTOR on downstream signaling and tumor growth in pancreatic cancer xenograft models. Cancer Biology & Therapy, 8(20), 1893–1901.CrossRef
99.
Zurück zum Zitat Chang, Q., Chapman, M. S., Miner, J. N., & Hedley, D. W. (2010). Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. BMC Cancer, 10, 515. doi:10.1186/1471-2407-10-515.PubMedCrossRef Chang, Q., Chapman, M. S., Miner, J. N., & Hedley, D. W. (2010). Antitumour activity of a potent MEK inhibitor RDEA119/BAY 869766 combined with rapamycin in human orthotopic primary pancreatic cancer xenografts. BMC Cancer, 10, 515. doi:10.​1186/​1471-2407-10-515.PubMedCrossRef
100.
Zurück zum Zitat Hatzivassiliou, G., Liu, B., O’Brien, C., Spoerke, J. M., Hoeflich, K. P., Haverty, P. M., et al. (2012). ERK inhibition overcomes acquired resistance to MEK inhibitors. Molecular Cancer Therapeutics, 11(5), 1143–1154. doi:10.1158/1535-7163.MCT-11-1010.PubMedCrossRef Hatzivassiliou, G., Liu, B., O’Brien, C., Spoerke, J. M., Hoeflich, K. P., Haverty, P. M., et al. (2012). ERK inhibition overcomes acquired resistance to MEK inhibitors. Molecular Cancer Therapeutics, 11(5), 1143–1154. doi:10.​1158/​1535-7163.​MCT-11-1010.PubMedCrossRef
Metadaten
Titel
Targeting the Ras–ERK pathway in pancreatic adenocarcinoma
verfasst von
Cindy Neuzillet
Pascal Hammel
Annemilaï Tijeras-Raballand
Anne Couvelard
Eric Raymond
Publikationsdatum
01.06.2013
Verlag
Springer US
Erschienen in
Cancer and Metastasis Reviews / Ausgabe 1-2/2013
Print ISSN: 0167-7659
Elektronische ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-012-9396-2

Weitere Artikel der Ausgabe 1-2/2013

Cancer and Metastasis Reviews 1-2/2013 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.