Efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from leveraging combination approaches. This study compared the anti-tumor response of combining the SOS1-KRAS interaction inhibitor, BI-3406, 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 induced a stronger anti-tumor response than KRAS G12C i alone, comparable to other combinations. This enhanced response was associated with stronger and extended RAS-MAPK signaling suppression. Importantly, the combination delayed acquired adagrasib resistance and re-established anti-proliferative activity in resistant CRC models. These findings suggest KRAS G12C plus SOS1 inhibition as a promising therapeutic strategy.

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