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

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(G12C)i) to those induced by KRAS(G12C)i alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS(G12C)i induces an anti-tumor response stronger than that observed with KRAS(G12C)i 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(G12C)i 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 KRAS(G12C)i-resistant CRC models. Our findings position KRAS(G12C) plus SOS1 inhibition therapy as a promising strategy for treating both KRAS(G12C)-mutated tumors as well as for addressing acquired resistance to KRAS(G12C)i.