Co-targeting SOS1 enhances the antitumor effects of KRAS^G12C inhibitors by addressing intrinsic and acquired resistance.

ABSTRACT: Combination approaches are needed to strengthen and extend the clinical response to KRAS^G12C inhibitors (KRAS^G12Ci). Here, we assessed the antitumor responses of KRAS^G12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS^G12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRAS^G12Ci seemed to be driven by upregulation of MR

SUBMITTER: Thatikonda V 

PROVIDER: S-EPMC11424490 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature