Abstract B37: Concomitant blockade of glucose uptake and paracrine HGF signaling uncovers the metabolic vulnerability of KRAS-mutant colorectal tumors

Abstract

Abstract Mutations in KRAS and over-expression of MET, the hepatocyte growth factor (HGF) receptor, are both negative prognostic factors for colorectal cancer (CRC). We studied the KRAS-MET interplay using human isogenic CRC cells with defined KRAS status and human HGF knock-in SCID mice, thereby reproducing species-specific HGF-MET paracrine signaling. We show that KRAS-mutant CRC cells display an extraordinary high glycolytic rate that makes them ‘addicted’ to glycolysis. When glucose availability is scarce or upon drug-mediated impairment of glucose metabolism, KRAS-mutant cells rapidly undergo apoptosis, unless ‘salvaged’ by micro-environment-borne HGF, which permits their survival by enhancing glucose influx, sustaining glycolysis and activating autophagy, thus improving energetic efficiency and preventing a mitotic catastrophe. In an orthotopic model of metastatic CRC using human HGF knock-in SCID mice and human KRAS-mutant CRC cells, combined pharmacological blockade of glucose metabolism and of HGF/MET signaling resulted in synthetic lethality and achieved superior tumor inhibition and metastasis suppression compared to metabolism-active drugs or HGF/MET inhibitors alone. In the same system, paracrine HGF signaling also protected KRAS-mutant tumors against anti-angiogenic therapy, which caused more dramatic and less specific metabolic stress by depriving tumors of both nutrients and oxygen. However, in contrast to selective glucose metabolism impairment, anti-angiogenic therapy exacerbated tumor hypoxia, promoted HGF-dependent metastatic dissemination and gave rise to acquired resistance. These results indicate that selective impairment of glucose metabolism is a much safer and more effective approach to target KRAS-mutant CRC metabolic vulnerability compared to angiogenesis inhibition. They also show that microenvironment-borne HGF is a major source of resistance to anti-tumor therapies that cause metabolic stress to cancer cells. Considering that angiogenesis inhibition is the only biological therapy currently available for KRAS-mutant tumors, the data generated by this study open new perspectives for the treatment of this highly aggressive cancer type. Citation Format: Alessia Mira, Paolo Michieli. Concomitant blockade of glucose uptake and paracrine HGF signaling uncovers the metabolic vulnerability of KRAS-mutant colorectal tumors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B37.