JCT  Vol.4 No.6 , August 2013
Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer
Abstract: Epidermal growth factor receptor inhibitors have shown promise in the treatment of colorectal cancers. However, activating KRAS mutations cause primary resistance to these agents and contribute to cancer progression. Downstream signaling of oncogenic KRAS induces activation of HIF-1α and HIF-2α which in turn activate genes that promote cell proliferation, obstruct cell death, and induce angiogenesis and metabolic adaptation. We will discuss clinical trial results with EGFR inhibitors, mechanism of resistance mediated by oncogenic KRAS, and strategies under clinical development to overcome KRAS-mediated resistance.
Cite this paper: E. Gupta, N. Santos, Y. Liu, P. Havre, N. Dang, H. Luesch and L. Dang, "Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer," Journal of Cancer Therapy, Vol. 4 No. 6, 2013, pp. 1132-1139. doi: 10.4236/jct.2013.46129.

[1]   A. Wouters, C. Boeckx, J. B. Vermorken, D. V. den Weyngaert, M. Peeters and F. Lardon, “The Intriguing Interplay between Therapies Targeting the Epidermal Growth Factor Receptor, the Hypoxic Microenvironment and Hypoxia-Inducible Factors,” Current Pharmaceutical Design, Vol. 19, No. 5, 2012, pp. 907-917.

[2]   H. Lu, K. Liang, Y. Lu and Z. Fan, “The Anti-EGFR Antibody Cetuximab Sensitizes Human Head and Neck Squamous Cell Carcinoma Cells to Radiation in Part through Inhibiting Radiation-Induced Upregulation of HIF-1alpha,” Cancer Letters, Vol. 322, No. 1, 2012, pp. 78-85. doi:10.1016/j.canlet.2012.02.012

[3]   L. Xu, M. B. Nilsson, P. Saintigny, T. Cascone, M. H. Herynk, Z. Du, et al., “Epidermal Growth Factor Receptor Regulates MET Levels and Invasiveness through Hypoxia-Inducible Factor-1alpha in Non-Small Cell Lung Cancer Cells,” Oncogene, Vol. 29, No. 18, 2010, pp. 2616-2627. doi:10.1038/onc.2010.16

[4]   A. Franovic, C. E. Holterman, J. Payette and S. Lee, “Human Cancers Converge at the HIF-2alpha Oncogenic Axis,” Proceedings of the National Academy of Sciences of USA, Vol. 106, No. 50, 2009, pp. 21306-21311. doi:10.1073/pnas.0906432106

[5]   D. L. Wheeler, E. F. Dunn and P. M. Harari, “Understanding Resistance to EGFR Inhibitors-Impact on Future Treatment Strategies,” Nature Reviews Clinical Oncology, Vol. 7, No. 9, 2010, pp. 493-507. doi:10.1038/nrclinonc.2010.97

[6]   H. Modjtahedi and S. Essapen, “Epidermal Growth Factor Receptor Inhibitors in Cancer Treatment: Advances, Challenges and Opportunities,” Anticancer Drugs, Vol. 20, No. 10, 2009, pp. 851-855. doi:10.1097/CAD.0b013e3283330590

[7]   R. Bianco, G. Daniele, F. Ciardiello and G. Tortora, “Monoclonal Antibodies Targeting the Epidermal Growth Factor Receptor,” Current Drug Targets, Vol. 6, No. 3, 2005, pp. 275-287. doi:10.2174/1389450053765842

[8]   J. Tol, M. Koopman, A. Cats, C. J. Rodenburg, G. J. Creemers, J. G. Schrama, et al., “Chemotherapy, Bevacizumab, and Cetuximab in Metastatic Colorectal Cancer,” The New England Journal of Medicine, Vol. 360, No. 6, 2009, pp. 563-572. doi:10.1056/NEJMoa0808268

[9]   C. Bokemeyer, I. Bondarenko, A. Makhson, J. T. Hartmann, J. Aparicio, F. de Braud, et al., “Fluorouracil, Leucovorin, and Oxaliplatin with and without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 27, No. 5, 2009, pp. 663-671. doi:10.1200/JCO.2008.20.8397

[10]   C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. de Braud, G. Schuch, A. Zubel, et al., “Efficacy According to Biomarker Status of Cetuximab plus FOLFOX-4 as First-Line Treatment for Metastatic Colorectal Cancer: The OPUS Study,” Annals of Oncology, Vol. 22, No. 7, 2011, pp. 1535-1546. doi:10.1093/annonc/mdq632

[11]   W. De Roock, B. Claes, D. Bernasconi, J. De Schutter, B. Biesmans, G. Fountzilas, et al., “Effects of KRAS, BRAF, NRAS, and PIK3CA Mutations on the Efficacy of Cetuximab plus Chemotherapy in Chemotherapy-Refractory Metastatic Colorectal Cancer: A Retrospective Consortium Analysis,” Lancet Oncology, Vol. 11, No. 8, 2010, pp. 753-762. doi:10.1016/S1470-2045(10)70130-3

[12]   E. Van Cutsem, C. H. Kohne, E. Hitre, J. Zaluski, C. R. C. Chien, A. Makhson, et al., “Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer,” The New England Journal of Medicine, Vol. 360, No. 14, 2009, pp. 1408-1417. doi:10.1056/NEJMoa0805019

[13]   E. Van Cutsem, C. H. Kohne, I. Lang, G. Folprecht, M. P. Nowacki, S. Cascinu, 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,” Journal of Clinical Oncology, Vol. 29, No. 15, 2011, pp. 2011-2019. doi:10.1200/JCO.2010.33.5091

[14]   G. Colucci, F. Giuliani, C. Garufi, R. Mattioli, L. Manzione, A. Russo, et al., “Cetuximab plus FOLFOX-4 in Untreated Patients with Advanced Colorectal Cancer: A Gruppo Oncologico dell’Italia Meridionale Multicenter Phase II Study,” Oncology, Vol. 79, No. 5-6, 2010, pp. 415-422. doi:10.1159/000323279

[15]   G. Folprecht, T. Gruenberger, W. O. Bechstein, H. R. Raab, F. Lordick, J. T. Hartmann, et al., “Tumour Response and Secondary Resectability of Colorectal Liver Metastases Following Neoadjuvant Chemotherapy with Cetuximab: The CELIM Randomised Phase 2 Trial,” Lancet Oncology, Vol. 11, No. 1, 2010, pp. 38-47. doi:10.1016/S1470-2045(09)70330-4

[16]   J. Ocvirk, T. Brodowicz, F. Wrba, T. E. Ciuleanu, G. Kurteva, S. Beslija, et al., “Cetuximab plus FOLFOX6 or FOLFIRI in Metastatic Colorectal Cancer: CECOG Trial,” World Journal of Gastroenterology, Vol. 16, No. 25, 2010, pp. 3133-43. doi:10.3748/wjg.v16.i25.3133

[17]   T. S. Maughan, R. A. Adams, C. G. Smith, A. M. Meade, M. T. Seymour, R. H. Wilson, et al., “Addition of Cetuximab to Oxaliplatin-Based First-Line Combination Chemotherapy for Treatment of Advanced Colorectal Cancer: Results of the Randomised Phase 3 MRC COIN Trial,” Lancet, Vol. 377, No. 9783, 2011, pp. 2103-2114. doi:10.1016/S0140-6736(11)60613-2

[18]   N. Moosmann, L. F. von Weikersthal, U. Vehling-Kaiser, M. Stauch, H. G. Hass, H. Dietzfelbinger, et al., “Cetuximab plus Capecitabine and Irinotecan Compared with Cetuximab plus Capecitabine and Oxaliplatin as FirstLine Treatment for Patients with Metastatic Colorectal Cancer: AIO KRK-0104—A Randomized Trial of the German AIO CRC Study Group,” Journal of Clinical Oncology, Vol. 29, No. 8, 2011, pp. 1050-1058. doi:10.1200/JCO.2010.31.1936

[19]   M. Peeters, T. J. Price, A. Cervantes, A. F. Sobrero, M. Ducreux, Y. Hotko, et al., “Randomized Phase III Study of Panitumumab with Fluorouracil, Leucovorin, and Irinotecan (FOLFIRI) Compared with FOLFIRI alone as Second-Line Treatment in Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 28, No. 31, 2010, pp. 4706-4713. doi:10.1200/JCO.2009.27.6055

[20]   J. Y. Douillard, S. Siena, J. Cassidy, J. Tabernero, R. Burkes, M. Barugel, et al., “Randomized, Phase III Trial of Panitumumab with Infusional Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX4) versus FOLFOX4 alone as First-Line Treatment in Patients with Previously Untreated metastatic Colorectal Cancer: The PRIME Study,” Journal of Clinical Oncology, Vol. 28, No. 31, 2010, pp. 4697-4705. doi:10.1200/JCO.2009.27.4860

[21]   A. L. Cohn, G. C. Shumaker, P. Khandelwal, D. A. Smith, M. A. Neubauer, N. Mehta, et al., “An Open-Label, SingleArm, Phase 2 Trial of Panitumumab plus FOLFIRI as Second-Line Therapy in Patients with Metastatic Colorectal Cancer,” Clinical Colorectal Cancer, Vol. 10, No. 3, 2011, pp. 171-177. doi:10.1016/j.clcc.2011.03.022

[22]   J. R. Hecht, E. Mitchell, M. A. Neubauer, H. A. Burris, P. Swanson, T. Lopez, et al., “Lack of Correlation between Epidermal Growth Factor Receptor Status and Response to Panitumumab Monotherapy in Metastatic Colorectal Cancer,” Clinical Cancer Research, Vol. 16, No. 7, 2010, pp. 2205-2213. doi:10.1158/1078-0432.CCR-09-2017

[23]   R. G. Amado, M. Wolf, M. Peeters, E. Van Cutsem, S. Siena, D. J. Freeman, et al., “Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 26, No. 10, 2008, pp. 1626-1634. doi:10.1200/JCO.2007.14.7116

[24]   B. B. Friday and A. A. Adjei, “K-Ras as a Target for Cancer Therapy,” Biochimica et Biophysica Acta, Vol. 1756, No. 2, 2005, pp. 127-144.

[25]   R. Blum, J. Jacob-Hirsch, N. Amariglio, G. Rechavi and Y. Kloog, “Ras Inhibition in Glioblastoma Down-Regulates Hypoxia-Inducible Factor-1alpha, Causing Glycolysis Shutdown and Cell Death,” Cancer Research, Vol. 65, No. 3, 2005, pp. 999-1006.

[26]   H. E. Ryan, M. Poloni, W. McNulty, D. Elson, M. Gassmann, J. M. Arbeit, et al., “Hypoxia-Inducible Factor1alpha Is a Positive Factor in Solid Tumor Growth,” Cancer Research, Vol. 60, No. 15, 2000, pp. 4010-4015.

[27]   H. J. An, O. Maeng, K. H. Kang, J. O. Lee, Y. S. Kim, S. G. Paik, et al., “Activation of Ras Up-Regulates ProApoptotic BNIP3 in Nitric Oxide-Induced Cell Death,” The Journal of Biological Chemistry, Vol. 281, No. 45, 2006, pp. 33939-33948. doi:10.1074/jbc.M605819200

[28]   S. Y. Chun, C. Johnson, J. G. Washburn, M. R. Cruz-Correa, D. T. Dang and L. H. Dang, “Oncogenic KRAS Modulates Mitochondrial Metabolism in Human Colon Cancer Cells by Inducing HIF-1a and HIF-2a Target Genes,” Molecular Cancer, Vol. 9, 2010, p. 293.

[29]   G. L. Semenza, “Targeting HIF-1 for Cancer Therapy,” Nature Reviews Cancer, Vol. 3, No. 10, 2003, pp. 721-732. doi:10.1038/nrc1187

[30]   A. L. Harris, “Hypoxia—A Key Regulatory Factor in Tumour Growth,” Nature Reviews Cancer, Vol. 2, No. 1, 2002, pp. 38-47. doi:10.1038/nrc704

[31]   G. L. Semenza, “HIF-1 Inhibitors for Cancer Therapy: From Gene Expression to Drug Discovery,” Current Pharmaceutical Design, Vol. 15, No. 33, 2009, pp. 3839-3843. doi:10.2174/138161209789649402

[32]   G. Melillo, “Hypoxia-Inducible Factor 1 Inhibitors,” Methods in Enzymology, Vol. 435, 2007, pp. 385-402. doi:10.1016/S0076-6879(07)35020-9

[33]   D. Escuin, J. W. Simons and P. Giannakakou, “Exploitation of the HIF Axis for Cancer Therapy,” Cancer Biology & Therapy, Vol. 3, No. 7, 2004, pp. 608-611. doi:10.4161/cbt.3.7.954

[34]   A. Giaccia, B. G. Siim and R. S. Johnson, “HIF-1 as a Target for Drug Development,” Nature Reviews Drug Discovery, Vol. 2, No. 10, 2003, pp. 803-811. doi:10.1038/nrd1199