Adrienne D. Cox1,2,3 and Channing J. Der1,3 1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; 2Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA; 3Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA Corresponding authors: cjdermed.unc.edu, adrienne_coxmed.unc.edu Abstract

The three RAS genes (HRAS, KRAS, and NRAS) comprise the most frequently mutated oncogene family in cancer. KRAS is the predominant isoform mutated in cancer and is most prevalently mutated in major causes of cancer deaths including lung, colorectal, and pancreatic cancers. Despite extensive academic and industry efforts to target KRAS, it would take nearly four decades before approval of the first clinically effective KRAS inhibitors for the treatment of KRAS mutant lung cancer. We revisit past anti-KRAS strategies and painful lessons learned and then focus on the rapidly evolving landscape of direct RAS inhibitors, resistance mechanisms, and potential combination treatments.