Targeting HIF-1α and HIF-2α to Overcome Treatment Resistance Mediated by Oncogenic KRAS in Colorectal Cancer *

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.