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.

Venu Thatikonda, Hengyu Lu, Sabine Jurado, Kaja Kostyrko, Christopher A Bristow, Karin Bosch, Ningping Feng, Sisi Gao, Daniel Gerlach, Michael Gmachl, Simone Lieb, Astrid Jeschko, Annette A Machado, Ethan D Marszalek, Mikhila Mahendra, Philipp A Jaeger, Alexey Sorokin, Sandra Strauss, Francesca Trapani, Scott Kopetz, Christopher P Vellano, Mark Petronczki, Norbert Kraut, Timothy P Heffernan, Joseph R Marszalek, Mark Pearson, Irene Waizenegger, Marco H Hofmann