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RAS  (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including  RAS , RAF, MEK, and ERK, have demonstrated activity in  BRAF  mutant and, in limited cases,  RAS  mutant cancer.  RAS  mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to  RAS  mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.

Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer