Positive feedback between oncogenic KRAS and HIF-1α confers drug resistance in colorectal cancer

Abstract

Yanzhao Wang,1 Fuming Lei,2 Wanshui Rong,2 Qingmin Zeng,2 Wenbing Sun1 1Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of General Surgery, Peking University Shougang Hospital, Beijing, People’s Republic of China Abstract: Approximately 30%–50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study, we sought to determine whether resistance to EGFR inhibitors in colorectal cancer cells harboring KRAS G12V mutation is associated with hypoxia. Our data indicated that HIF-1α was induced by KRAS G12V signaling at transcription level. Hypoxia or HIF-1α overexpression could increase KRAS G12V activity. Therefore, a positive feedback between hypoxia and KRAS G12V activation was formed. Cetuximab, an EGFR inhibitor, which has a minor effect on KRAS-mutant CRCs, could effectively inhibit the proliferation of CRC cells harboring KRAS G12V mutation when combined with HIF-1α inhibitor PX-478. Our data indicated that hypoxia was involved in resistance to anti-EGFR therapy, and a combination therapy might be necessary for CRC patients with KRAS mutation. Keywords: combination therapy, EGFR inhibitor resistance, KRAS G12V