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Researchers discovered that divarasib, a clinical KRAS G12C inhibitor used to treat lung cancer, unexpectedly binds to and stabilizes RBM39, an essential RNA splicing protein. This off-target interaction interferes with drugs designed to degrade RBM39, affects insulin receptor signaling through altered gene expression and splicing, and contributes to both the therapeutic effects and toxicities of divarasib. The findings reveal a previously unknown mechanism by which this cancer drug influences cell behavior beyond its intended KRAS target.
Why it matters
This discovery helps explain why patients respond differently to KRAS G12C inhibitors and experience certain side effects. Understanding this off-target interaction could guide development of improved cancer drugs, inform combination therapy strategies, and potentially explain drug resistance mechanisms in lung cancer treatment.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
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.
Source: The KRAS G12C Inhibitor Divarasib Stabilizes RBM39 and Antagonizes Aryl-Sulfonamide Degraders