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

Combination approaches are needed to strengthen and extend the clinical response to KRAS inhibitors (KRASi). 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.

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.

The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy.

Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal amplification being responsible for some of these cases.