Faculty, Staff and Student Publications
Publication Date
9-1-2024
Journal
Nature Cancer
Abstract
Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal cancer models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C 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. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.
Keywords
SOS1 Protein, Proto-Oncogene Proteins p21(ras), Humans, Drug Resistance, Neoplasm, Animals, Mice, Cell Line, Tumor, Colorectal Neoplasms, Xenograft Model Antitumor Assays, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Lung Neoplasms, Mutation, Female, Antineoplastic Combined Chemotherapy Protocols, Acetonitriles, Piperazines, Pyrimidines, Cancer therapy, Cancer therapeutic resistance, Cancer
DOI
10.1038/s43018-024-00800-6
PMID
39103541
PMCID
PMC11424490
PubMedCentral® Posted Date
8-5-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons