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

Combination approaches are needed to strengthen and extend the clinical response to KRAS inhibitors (KRAS i). Here, we assessed the antitumor responses of KRAS mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRAS 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 i seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRAS i treatment. These results suggest KRAS plus SOS1i to be a promising strategy for treating both KRAS i naive and relapsed KRAS -mutant tumors.