other-cancer

KRAS inhibitors show dramatic effectiveness in appendiceal cancer — a rare tumor with almost no treatment options

Appendiceal adenocarcinoma (AA) is a rare cancer with very limited treatment options. KRAS is the most commonly mutated gene in AA, making KRAS inhibitors a logical therapeutic target, but no preclinical or clinical data existed for this cancer type.

Dan Manning

Dan Manning

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KRAS inhibitors show dramatic effectiveness in appendiceal cancer — a rare tumor with almost no treatment options

KRAS inhibitors show dramatic effectiveness in appendiceal cancer — a rare tumor with almost no treatment options

Appendiceal adenocarcinoma (AA) is a rare cancer with very limited treatment options. KRAS is the most commonly mutated gene in AA, making KRAS inhibitors a logical therapeutic target, but no preclinical or clinical data existed for this cancer type.

Researchers tested two KRAS inhibitors — MRTX1133 (KRAS-G12D specific) and RMC-6236 (pan-KRAS) — in patient-derived organoid and orthotopic tumor models of AA. Both showed impressive potency at nanomolar concentrations. Multi-omics profiling characterized how tumors responded at the molecular level. Critically, the researchers also treated six real patients with heavily pre-treated appendiceal cancer using KRAS inhibitors and assessed clinical outcomes.

This is one of the first reports connecting preclinical KRAS inhibitor data in AA to actual patient responses, making it particularly significant for this orphan indication. Given how few options patients with this cancer have, KRAS inhibitor trials in AA could significantly change management of the disease.

Key Findings

  • MRTX1133 (KRAS-G12D inhibitor) showed potency at IC50=4.1 nM in appendiceal organoids
  • RMC-6236 (pan-KRAS inhibitor) effective against both KRAS-G12D and KRAS-G12V organoids
  • Orthotopic patient-derived xenograft models confirmed KRAS inhibitor effectiveness
  • Multi-omics profiling characterized tumor-intrinsic and microenvironmental responses
  • Six heavily pre-treated AA patients treated with KRAS inhibitors showed assessable clinical responses

Implications

For a cancer type with almost no approved therapies and poor outcomes, these findings provide strong preclinical rationale and initial clinical data supporting KRAS inhibitor use in appendiceal adenocarcinoma. This should accelerate inclusion of AA patients in KRAS inhibitor trials and potentially lead to dedicated clinical studies.

Caveats

Preprint, not peer reviewed. Patient cohort of 6 is very small. Clinical outcome data details are not visible in abstract. Preclinical models may not fully recapitulate human tumor biology. Summary based on abstract only.

Source: bioRxiv — 2026-04-10

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