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Researchers have identified that DIRAS3, an endogenous tumor suppressor protein, can directly inhibit multiple oncogenic KRAS variants through a specific molecular interface while largely sparing normal KRAS function. They developed a conformationally constrained peptide mimetic of DIRAS3's alpha-5 region that successfully suppresses KRAS signaling across diverse hotspot mutations, including G12 and Q61 variants, by disrupting KRAS interactions with downstream effectors and altering its membrane organization. This mimetic demonstrated broad efficacy against KRAS variants that show reduced sensitivity to current targeted therapies and suppressed tumor growth in animal models.
Why it matters
This work presents a novel therapeutic strategy for targeting oncogenic KRAS mutations across multiple cancer types by mimicking a natural inhibitory mechanism rather than direct KRAS binding. The approach may overcome limitations of current KRAS inhibitors that are variant-specific or show reduced effectiveness against certain mutations like Q61, potentially offering broader treatment options for KRAS-driven cancers.
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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.
Despite major advances in KRAS-directed therapies, broadly suppressing oncogenic KRAS signaling across diverse hotspot variants remains an unmet challenge. Here, we identify an endogenous inhibitory mechanism that suppresses signaling across the major oncogenic KRAS hotspot classes while largely sparing basal wild-type KRAS, revealing activation-state-selective inhibition. We demonstrate that the imprinted tumor suppressor DIRAS3 directly engages activated KRAS through a functionally defined inhibitory interface that can be molecularly mimicked to broadly inhibit KRAS-driven signaling. Using genetically controlled RASless reconstitution models, complementary cancer cell validation, structure-function analyses, molecular dynamics-based membrane topology modeling, and ultrastructural imaging, we show that dual lipid modification constrains DIRAS3 membrane topology, enabling an 5-encoded inhibitory interface to engage activated KRAS, disrupt signaling-competent membrane assemblies, and suppress downstream signaling. Structure-function analyses establish this interface as a critical determinant of DIRAS3-mediated KRAS inhibition. A conformationally constrained 5 mimetic recapitulates full-length DIRAS3 activity, broadly suppressing MAPK and PI3K signaling across multiple oncogenic KRAS variants, including Q61 mutants with reduced sensitivity to current tri-complex RAS(ON) inhibitors. Mechanistically, immunoprecipitation shows that the 5 mimetic reduces KRAS association with both RAF1 and p110 similarly across G12 and Q61 mutants, whereas RMC-7977 reduces inhibition of p110 association with Q61 KRAS. The 5 mimetic also disrupts KRAS nanocluster organization and inhibits tumor growth in vivo. These findings identify a targetable inhibitory interface within DIRAS3 and establish mimicry of an endogenous KRAS suppressor as a mechanistically distinct strategy for broad KRAS inhibition.