Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance

KRAS mutations drive resistance to targeted therapies, including EGFR inhibitors in colorectal cancer (CRC). Through genetic screens, we unexpectedly find that mutant HRAS , which is rarely found in CRC, is a stronger driver of resistance than mutant KRAS . This difference is ascribed to common codon bias in HRAS , which leads to much higher protein expression, and implies that the inherent poor expression of KRAS due to rare codons must be surmounted during drug resistance. In agreement, we demonstrate that primary resistance to cetuximab is dependent upon both KRAS mutational status and protein expression level, and acquired resistance is often associated with KRAS Q61 mutations that function even when protein expression is low. Finally, cancer cells upregulate translation to facilitate KRAS G12 -driven acquired resistance, resulting in hypersensitivity to translational inhibitors. These findings demonstrate that codon bias plays a critical role in KRAS -driven resistance and provide a rationale for targeting translation to overcome resistance. KRAS mutations drive resistance to diverse targeted therapies. In this study, the authors show that the rare codons of KRAS , yielding low oncogene expression, can be overcome to drive resistance to anti-EGFR therapy in CRC through upregulation of global translation or through selection of more potent KRAS Q61 mutations.