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Updated: Apr 26, 2026

Establishment of Hepatocarcinoma in BALB/c-nu Mice and Investigation of the Therapeutic Effect of the Sanleng Jiashen Formula
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Establishment of Hepatocarcinoma in BALB/c-nu Mice and Investigation of the Therapeutic Effect of the Sanleng Jiashen Formula

Published on: January 26, 2024

861

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

Rodrigo Entrialgo-Cadierno1, Konstantina Morali1, Iker Feliu1

  • 1Program in Solid Tumors, Center for Applied Medical Research (CIMA)-University of Navarra, 31008 Pamplona, Navarra, Spain.

Cancer Cell
|April 24, 2026
PubMed

Insights

RAS(ON) multi-selective inhibitors show promise for treating KRAS-mutant cholangiocarcinoma (CCA). These drugs target the active RAS-GTP state, demonstrating anticancer effects in preclinical models and early clinical activity in patients with advanced CCA.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Cholangiocarcinoma (CCA) frequently harbors KRAS mutations, driving tumor growth.
  • Targeting the active GTP-bound state of RAS proteins offers a therapeutic strategy.

Purpose of the Study:

  • To investigate the efficacy of RAS(ON) multi-selective inhibitors in KRAS-mutant CCA.
  • To evaluate the clinical activity of daraxonrasib in patients with advanced KRAS G12 CCA.
  • To explore resistance mechanisms and combination strategies.

Main Methods:

  • Preclinical studies using cell- and patient-derived xenografts and immunocompetent allograft models.
  • Clinical evaluation of daraxonrasib in patients with advanced KRAS G12 CCA.
  • Assessment of RAS-GTP inhibition in combination with standard-of-care regimens.
  • Analysis of intrinsic and acquired resistance mechanisms.

Main Results:

  • RAS(ON) multi-selective inhibitors demonstrated significant anticancer responses in preclinical models.
  • Clinical activity of daraxonrasib was observed in two patients with advanced KRAS G12 CCA.
  • RAS-GTP inhibition potentiated standard-of-care regimens, prolonging survival.
  • Resistance mechanisms primarily involve RAS signaling overactivation.

Conclusions:

  • KRAS-mutant CCA is dependent on RAS signaling for proliferation.
  • RAS-GTP inhibition is a promising therapeutic approach for KRAS-mutant CCA.
  • Further clinical evaluation of RAS-GTP inhibitors in CCA is warranted.
Keywords:
KRAS oncogeneRAS(ON) multi-selective inhibitorbiliary tract cancercholangiocarcinomadrug combinationspreclinical modelstargeted therapytherapy resistance

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