Although progress has been made in specifically targeting the KRAS-G12C mutant oncoprotein, there remains a need to directly target other mutant RAS proteins. Kobayashi et al. describe a role for silent mutations in creating functional KRAS-Q61K and develop a strategy that could potentially target this mutant as well as other RAS-Q61X mutations. In looking at KRAS mutations known to confer resistance to the EGFR inhibitor osimertinib in a lung cancer cell line, the authors discovered that only some alleles of the known resistance mutation KRAS~Q61K increased in frequency under osimertinib selection. These specific alleles contained a concurrent silent mutation at G60. Cells that carried both G60G and Q61K mutations (KRAS~GQ60GK), but not KRAS~Q61K cells, had high levels of RAS pathway activation, indicating that G60G was required for KRAS-Q6IK function.
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