Feedback activation of EGFR/wild-type RAS signaling axis limits KRAS^G12D inhibitor efficacy in KRAS^G12D-mutated colorectal cancer.

ABSTRACT: Colorectal cancer (CRC), which shows a high degree of heterogeneity, is the third most deadly cancer worldwide. Mutational activation of KRAS^G12D occurs in approximately 10-12% of CRC cases, but the susceptibility of KRAS^G12D-mutated CRC to the recently discovered KRAS^G12D inhibitor MRTX1133 has not been fully defined. Here, we report that MRTX1133 treatment caused reversible growth arrest in KRAS^G12D-mutated CRC cells, accompanied by partial reactivation of RAS effector signaling. Through a drug-anchored synthetic lethality screen, we discovered that epidermal growth factor receptor (EGFR) inhibition was synthetic lethal with MRTX1133. Mechanistically, MRTX1133 treatment downregulated the expression of ERBB receptor feedback inhibitor 1 (ERRFI1)

SUBMITTER: Feng J 

PROVIDER: S-EPMC10181928 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature