The KRAS G12C Inhibitor Divarasib Stabilizes RBM39 and Antagonizes Aryl-Sulfonamide Degraders

Authors

Chen, S.-Y., Zou, Y., Wu, J., Nam, G., Lee, H., Chen, Y., Federico, C., Setayeshpour, Y., Lin, C.-C., Wu, S.-C., Strickler, J. H., Hong, J., Fitzgerald, M. C., Chi, J.-T. A.

Abstract

KRAS G12C inhibitors have demonstrated meaningful clinical benefit in KRAS G12C-mutant non-small cell lung cancer (NSCLC), yet responses remain heterogeneous and treatment-associated toxicities persist for reasons that are incompletely understood. Cysteine profiling indicates that these covalent inhibitors are highly selective for mutant KRAS; however, such approaches cannot detect noncovalent engagement of additional non-RAS proteins. Here, we used a protein-folding stability profiling technique, stability of proteins from rates of oxidation (SPROX), to identify protein targets of the clinical KRAS G12C inhibitor, divarasib (GDC-6036), in KRAS-mutant NSCLC lysates. SPROX revealed a focused set of candidate interactors, including the essential splicing factor RBM39, which was reproducibly stabilized at both divarasib concentrations tested. We subsequently confirmed that divarasib directly and noncovalently binds to RBM39 protein. In NSCLC cells, divarasib increased RBM39 protein abundance and antagonized RBM39 degradation induced by the aryl-sulfonamide molecular glue indisulam through a post-transcriptional mechanism. Divarasib and RBM39 degraders reciprocally antagonized each other's cytotoxicity, and RBM39 knockdown modestly reduced divarasib-induced cell death. Mechanistically, divarasib-mediated RBM39 stabilization regulated both INSR expression and alternative splicing, altered downstream insulin receptor signaling, and contributed to divarasib-associated cytotoxicity. Consistent with these findings, RBM39 and INSR expression were positively correlated across multiple human cancer types. Collectively, these findings identify RBM39 as a previously unrecognized noncovalent target of divarasib and uncover an RBM39-INSR signaling axis that modulates cellular responses to both divarasib and RBM39 degraders.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 21 Aug 2026.

Stats

1-terrible, 9-excellent. How would you rate this preprint? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.