The study, coordinated by Cima Universidad de Navarra in collaboration with Revolution Medicines, has been published in the scientific journal Cancer Cell. Researchers from Clínic-IDIBAPS involved in the study include Teresa Macarulla, Head of the Medical Oncology Department at Hospital Clínic and Head of the Upper Gastrointestinal Cancer Translational Oncology Group at IDIBAPS; Tian Tian, co-leader of the group; and José María Herranz, a group researcher, as well as Mariana Yáñez and Daniel Sin, who will soon be joining the IDIBAPS team.
A rare but highly aggressive cancer
Cholangiocarcinoma is a tumor that arises in the bile ducts, which carry bile from the liver to the intestine. Although it is considered a relatively rare cancer, its incidence is increasing and it is often diagnosed at advanced stages, limiting treatment options and leading to an unfavorable prognosis.
Approximately 25% of these tumors harbor mutations in the KRAS gene, a key oncogene involved in tumor cell proliferation. Despite its clinical relevance, no effective targeted therapies have been available to date for this subgroup of patients.
RAS inhibitors with antitumor activity
The study evaluates the effect of novel experimental drugs known as multiselective RAS(ON) inhibitors, which block the active form of the RAS protein. Using different preclinical models of cholangiocarcinoma, the researchers observed a strong antitumor effect in KRAS-mutant tumors, which are highly dependent on aberrant RAS signaling for growth and survival.
The findings indicate that pharmacological inhibition of this pathway can significantly slow tumor growth and opens the door to new therapeutic strategies for a cancer with a high unmet medical need.
Improved outcomes with combination therapies
To achieve deeper and more durable responses, the research team also explored combining RAS inhibitors with the current standard treatment for cholangiocarcinoma, which includes chemotherapy and immunotherapy.
The results show that these combinations enhance antitumor activity in preclinical models, delay tumor growth and improve survival compared with each treatment administered alone.
The work was carried out within the Cancer Center Clínica Universidad de Navarra and involved research teams from Clínic-IDIBAPS, VHIO, Biogipuzkoa and CIC, all affiliated with cooperative research networks such as CIBERONC and CIBEREHD.
The study was funded by Revolution Medicines, as well as by public funding from the Spanish Ministry of Science, Innovation and Universities, and private donations, including the José Baringo León fellowship.
Study reference:
Entrialgo-Cadierno R, Morali K, Feliu I, Wang Y, Evans JW, Yañez-Bartolome M, Lopez I, Macaya I, Cueto-Ureña C, Sin-Coscujuela D, Senent Y, Herranz JM, Raghulan R, Vaquero J, Banales JM, Macarulla T, Ponz-Sarvise M, Pechuan-Jorge X, Guruceaga E, Schumpp A, Garcia AV, Kim A, Herzberg BO, Azad N, Hegde A, Tian TV, Aronchik I, Singh M, Jiang J, Vicent S. Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma. Cancer Cell. 2026 Apr 23:S1535-6108(26)00174-1. doi: 10.1016/j.ccell.2026.03.020.
