Dual Targeting of Autophagy and MEK in KRAS Mutant Cancer.

In two recent articles, Kinsey et al. (Nature Medicine 2019;25:620-627) and Bryant et al. (Nature Medicine 2019;25:628-640) reported that inhibition of MEK-ERK signaling in KRAS-mutated cancers induced autophagic flux, presumably as a metabolic adaptation mechanism. Importantly, they demonstrated that autophagy blockade via chloroquine (CQ) or hydroxychloroquine (HCQ) enhanced the efficacy of MEK-ERK inhibition in various preclinical models of KRAS-driven cancers, providing a rational basis for future clinical evaluation of this combination therapy.