Combined KRAS^G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS^G12C-driven cancers by addressing intrinsic and acquired resistance.

ABSTRACT: Efforts to improve the anti-tumor response to KRAS^G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS^G12C inhibitor (KRAS^G12Ci) to those induced by KRAS^G12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS^G12Ci induces an anti-tumor response stronger than that observed with KRAS^G12Ci alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS^G12Ci treatment delays the

SUBMITTER: Thatikonda V 

PROVIDER: S-EPMC9900819 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature