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.
Competing Interests: Competing Interests V. Thatikonda, S. Jurado, K. Kostyrko, K. Bosch, D. Gerlach, M. Gmachl, S. Lieb, A. Jeschko, P. A. Jaeger, S. Strauss, F. Trapani, M. Pearson, I. Waizenegger, M. P. Petronczki, N. Kraut and M. H. Hofmann report grants from the Austrian Research Promotion Agency (FFG), receive personal fees from Boehringer Ingelheim (full-time employee) during the conduct of the study. M.H. Hofmann and M. Gmachl have been listed as inventor on patent applications for SOS1 inhibitors. A. Sorokin, S. Kopetz, H. Lu, A. A. Machado, M. Mahendra, E. D. Marszalek, S. Gao, N. Feng, C. A. Bristow, C. P. Vellano, T. P. Heffernan, and J. R. Marszalek report other from Boehringer Ingelheim (sponsored research) during the conduct of the study and this work was performed under a sponsored research collaboration between MD Anderson and Boehringer Ingelheim, for which the latter provided funding support. S. Kopetz has ownership interest in Lutris, Iylon, Frontier Medicines, Xilis, Navire and is a consultant for Genentech, EMD Serono, Merck, Holy Stone Healthcare, Novartis, Lilly, Boehringer Ingelheim, AstraZeneca/MedImmune, Bayer Health, Redx Pharma, Ipsen, HalioDx, Lutris, Jacobio, Pfizer, Repare Therapeutics, Inivata, GlaxoSmithKline, Jazz Pharmaceuticals, Iylon, Xilis, Abbvie, Amal Therapeutics, Gilead Sciences, Mirati Therapeutics, Flame Biosciences, Servier, Carina Biotech, Bicara Therapeutics, Endeavor BioMedicines, Numab, Johnson & Johnson/Janssen, Genomic Health, Frontier Medicines, Replimune, Taiho Pharmaceutical, Cardiff Oncology, Ono Pharmaceutical, Bristol-Myers Squibb-Medarex, Amgen, Tempus, Foundation Medicine, Harbinger Oncology, Inc, Takeda, CureTeq, Zentalis, Black Stone Therapeutics, NeoGenomics Laboratories, Accademia Nazionale Di Medicina, and receive research funding from Sanofi, Biocartis, Guardant Health, Array BioPharma, Genentech/Roche, EMD Serono, MedImmune, Novartis, Amgen, Lilly, Daiichi Sankyo. T. P. Heffernan receives advisory fees from Cullgen Inc. and Roivant Discovery.