Abstract
Efforts to improve the anti-tumor response to KRASG12C 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 KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci 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 KRASG12Ci 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 KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.
Competing Interest Statement
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.
