Pan-RAS Inhibitors: Mechanism, Coverage of KRAS Mutation Classes, and Current Evidence

This blog is in progress

Disclaimer This article is a product of my own research into the literature and collaboration with AI. I’m still checking for accuracy, and this is not medical advice.

Overview

In my previous article, KRAS-Mutated Colorectal Cancer: New Treatments, Realities, and What to Expect I explored the various promising treatments and clinical trial status for cancer patients with challenging KRAS mutations. One of these treatments are a class called Pan-RAS inhibitors, and I wanted to discuss this further.

Pan-RAS inhibitors—such as RMC-6236 (daraxonrasib)—represent a promising new frontier in targeting KRAS-driven cancers. Unlike mutation-specific drugs that only target G12C, these agents aim to inhibit active RAS across multiple isoforms and mutant alleles by exploiting a conformational mechanism. This post explores how they work, why they should theoretically cover most RAS mutations, and what evidence currently exists to support their effectiveness.

1. Mechanism of Action: The Pan-RAS “Tri-Complex” Strategy

  • Target: Active (GTP-bound) RAS, not the GDP-bound “off” state.
  • Key players:
    • A small molecule ligand with affinity for cyclophilin A (CypA)
    • Cyclophilin A (CypA): a host protein that forms a binary complex with the ligand
    • RAS-GTP: when active, its switch II/effector lobe surface is exposed
  • Mechanism:
    1. Ligand binds CypA → forms a binary ligand·CypA scaffold.
    2. That composite binds RAS-GTP → creates ternary tri-complex (ligand·CypA·RAS(ON)).
    3. This sterically blocks effector binding (e.g., RAF, PI3K), shutting down downstream signaling.
      (pubs.acs.org, pmc.ncbi.nlm.nih.gov)
  • Selectivity for GTP-bound RAS arises because:
    • GDP-bound RAS does not present the appropriate binding surface.
    • The tri-complex approach relies on cooperative affinity, not high affinity of the ligand alone.

Mechanism of a Pan-RAS inhibitor, showing how it binds to the active RAS-GTP state.

2. Mutation Coverage: Which KRAS Variants Are Targetable?

Theoretically Covered (Pan-RAS)

  • Common codon 12–13 mutations: G12D, G12V, G12S, G13D, etc.
  • Less common, non-codon-12 mutations: K117N, A146T (exon 4)
  • Wild-type RAS in tumors with RAS hyperactivation via upstream signals

Mechanistic Rationale

  • All active-state RAS alleles share structural features at the switch II/effector lobe, enabling tri-complex binding.
  • High-and continuous GTP-loading (e.g., fast nucleotide exchange for K117N) logically increases the pool of RAS in the ON state—thus increasing susceptibility to tri-complex binding.

Caveats

  • Codon-12/13 mutants (especially G12D/V) have been most rigorously studied; K117N/A146 exhibit distinct biophysical behavior and signaling output, potentially affecting drug sensitivity.
    (pmc.ncbi.nlm.nih.gov)
  • Experimental datasets show highest pharmacological potency in KRAS G12X models; data for rarer alleles remain sparse.

3. Evidence to Date

Preclinical Studies

  • Biochemical assays: Validate tri-complex formation and blockade of RAS–RAF binding across KRAS/NRAS alleles.
  • Cell line models:
    • Strong suppression of MAPK signaling in KRAS G12X and NRAS Q61 mutants.
    • Activity includes some wild-type RAS contexts when upstream drivers are hyperactive.
      (pmc.ncbi.nlm.nih.gov)
  • In vivo xenografts:
    • Tumor regressions in G12D/V lines.
    • Emerging data show efficacy in G12S, Q61R, and some WT-RAS-driven models.

Early Clinical Findings

  • Phase I (NCT05379985):
    • Reported acceptable safety and pharmacokinetics in patients with various RAS mutations.
    • Disease stabilization and tumor shrinkage reported in KRAS-mutant CRC and pancreatic cohorts.
      (clinicaltrials.gov, ir.revmed.com)
  • Abstract data (AACR, ASCO GI):
    • Dose-dependent inhibition of downstream RAS signaling in tumor biopsies.
    • Responses observed across multiple KRAS mutations, though most frequent in codon-12 cases.

4. Practical Perspective: Mutation-by-Mutation Breakdown

KRAS Mutation Likely Sensitivity to Pan-RAS Inhibitor Notes
G12D/G12V High Strong preclinical/vivo data; most potent coverage.
G12S/G13D Moderate to High Biochemical coverage inferred; less well characterized.
K117N/A146 Possible Active-state is elevated; data limited and context may vary.
Q61 Mutations Moderate Some suppression shown in NRAS Q61 models.
Wild-type RAS Variable Dependent on upstream activation; may require biomarker selection.

5. Conclusions & Considerations

  • Mechanistically broad: Pan-RAS inhibitors are well-designed to target the active state across multiple mutations—offering a unified approach where mutation-specific drugs cannot.
  • Most evidence today supports G12D/V coverage, with emerging proof-of-concept for rarer alleles.
  • Unknowns remain for less common mutations (K117N, A146T); cell-line and animal models are needed.
  • CRC-specific biology (high EGFR/SHP2 feedback, wild-type RAS redundancy) may limit monotherapy, calling for combination strategies (e.g. +EGFR, +MEK, +SHP2) to optimize efficacy.
  • Clinical experience is emerging, with early stabilization and tumor responses across mutation types—tumor type and co-mutations matter.

Final Thought

Pan-RAS inhibitors like RMC-6236 are a significant advance in KRAS-targeted therapy. They promise to address a broader mutation landscape than any previous generation of drugs. While G12D/V coverage looks strong, the real test will be through ongoing trials—especially for rarer variants like G12S and K117N.

Supplemental

Expanding on rarer KRAS mutations like K117N:

Mechanistically,RMC-6236 (daraxonrasib) should have activity against KRAS K117N, but the strength of that activity in CRC is uncertain and likely lower/less predictable than for common G12X alleles.

Why it should work (mechanism)

RMC-6236 is a pan-RAS, “RAS(ON)” tri-complex inhibitor: it binds active, GTP-loaded RAS and, via cyclophilin A recruitment, blocks effector engagement (e.g., RAF) across multiple RAS isoforms/alleles—not just G12C. That design is mutation-agnostic in principle. PMC ClinicalTrials.gov

K117N (exon 4) alters the nucleotide pocket: Lys117 normally stabilizes guanine and promotes hydrolysis; K117N enhances nucleotide exchange, shifting KRAS toward the GTP-bound (ON) state, which is exactly the state RMC-6236 targets. PMC

Nuances/caveats specific to K117N in CRC

  • Exon 4 mutants (K117N/A146) can show distinct biochemistry and signaling output compared with codon-12/13 mutants. Some models reported lower steady-state RAS-GTP despite increased exchange, alongside KRAS dependence and recurrent copy-number gain—so “how ON” the protein is can vary by context. This could modulate drug sensitivity to ON-state inhibitors. PMC AACR Journals
  • Early clinical/preclinical summaries of RMC-6236 show broad activity across RAS-mutant tumors, with strongest potency in KRAS G12X lines; activity “beyond KRAS G12X” (including NRAS Q61) has been demonstrated, but allele-specific data for K117N aren’t yet clearly reported. Thus, activity is plausible but not yet clinically proven for K117N mCRC. PMC Revolution Medicines
  • CRC biology (strong EGFR/SHP2-mediated feedback and WT-RAS signaling) can blunt RAS-pathway inhibitors; combinations (e.g., with EGFR/SHP2/MEK blockade) may be needed to maximize effect, regardless of the KRAS allele. PMC

Bottom line

From first principles and available data, K117N creates an ON-state KRAS that RMC-6236 is designed to hit, so mechanistic sensitivity is expected. However, direct K117N-specific clinical evidence in CRC is limited, and CRC-specific feedback loops may necessitate combinations. If you’re tracking this for patients or trial design, I’d classify K117N as biologically compatible with RMC-6236’s mechanism but evidence-limited pending allele-resolved readouts from ongoing trials. ClinicalTrials.gov