Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer — Oak Academic Publishing
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Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer
Mayo Clinic Florida, Jacksonville, USA
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Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
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Department of Medicinal Chemistry, University of Florida, Gainesville, USA
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Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
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Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
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Department of Medicinal Chemistry, University of Florida, Gainesville, USA
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Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
1 Mayo Clinic Florida, Jacksonville, USA
2 Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
3 Department of Medicinal Chemistry, University of Florida, Gainesville, USA
4 Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
5 Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
6 Department of Medicinal Chemistry, University of Florida, Gainesville, USA
7 Division of Hematology/Oncology, Department of Internal Medicine, University of Florida Shands Cancer Center, University of Florida, Gainesville, USA
Epidermal growth factor receptor inhibitors have shown promise in the treatment of colorectal cancers. However, acti vating KRAS mutations cause primary resistance to these agents and contribute to cancer progression. Downstream signaling of oncogenic KRAS induces activation of HIF-1 α and HIF-2 α 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 develop ment to overcome KRAS-mediated resistance.
KeywordsColon CancerEGFRKRASHIF-1αHIF-2
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