RAS-driven colorectal cancer relies on glucose metabolism to support uncontrolled growth.However,monotherapy with glycolysis inhibitors like 2-deoxy-D-glucose causes limited effectiveness.Recent studies suggest that anti-tumor effects of glycolysis inhibition could be improved by combination treatment with inhibitors of oxidative phosphorylation.In this study we investigated the effect of a combination of 2-deoxy-D-glucose with lovastatin (a known inhibitor of mevalonate pathway and oxidative phosphorylation)on growth of KRAS-mutant human colorectal cancer cell lines HCT116 and LoVo.A combination of lovastatin (＞3.75 μM) and 2-deoxy-D-glucose (＞1.25 mM) synergistically reduced cell viability,arrested cells in the G2/M phase,and induced apoptosis.The combined treatment also reduced cellular oxygen consumption and extracellular acidification rate,resulting in decreased production of ATP and lower steady-state ATP levels.Energy depletion markedly activated AMPK,inhibited mTOR and RAS signaling pathways,eventually inducing autophagy,the cellular pro-survival process under metabolic stress,whereas inhibition of autophagy by chloroquine (6.25 μM) enhanced the cytotoxic effect of the combination of Iovastatin and 2-deoxy-D-glucose.These in vitro experiment results were reproduced in a nude mouse xenograft model of HCT116 cells.Our findings suggest that concurrently targeting glycolysis,oxidative phosphorylation,and autophagy may be a promising regimen for the management of RAS-driven colorectal cancers.