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

Efforts to improve the anti-tumor response to KRAS 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 inhibitor (KRASi) to those induced by KRASi alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASi induces an anti-tumor response stronger than that observed with KRASi 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 KRASi treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRASi-resistant CRC models. Our findings position KRAS plus SOS1 inhibition therapy as a promising strategy for treating both KRAS-mutated tumors as well as for addressing acquired resistance to KRASi.