Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

Rodrigo Entrialgo-Cadierno; Konstantina Morali; Iker Feliu; Yingyun Wang; James W. Evans; Mariana Yañez-Bartolome; Ines Lopez; Irati Macaya; Cristina Cueto-Ureña; Daniel Sin-Coscujuela; Yaiza Senent; Jose M. Herranz; Rashi Raghulan; Javier Vaquero; Jesus M. Banales; Teresa Macarulla; Mariano Ponz-Sarvise; Ximo Pechuan-Jorge; Elisabeth Guruceaga; Alyssa Schumpp; Alia V. Garcia; Alyssa Kim; Benjamin O. Herzberg; Nilofer Azad; Aparna Hegde; Tian V. Tian; Ida Aronchik; Mallika Singh; Jingjing Jiang; Silve Vicent

doi:10.1016/j.ccell.2026.03.020

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

Rodrigo Entrialgo-Cadierno
, Konstantina Morali
, Iker Feliu
, Yingyun Wang
, James W. Evans
, Mariana Yañez-Bartolome
, Ines Lopez
, Irati Macaya
, Cristina Cueto-Ureña
, Daniel Sin-Coscujuela
, Yaiza Senent
, Jose M. Herranz
, Rashi Raghulan
, Javier Vaquero
, Jesus M. Banales
, Teresa Macarulla
, Mariano Ponz-Sarvise
, Ximo Pechuan-Jorge
, Elisabeth Guruceaga
, Alyssa Schumpp

Alia V. Garcia, Alyssa Kim, Benjamin O. Herzberg, Nilofer Azad, Aparna Hegde, Tian V. Tian, Ida Aronchik, Mallika Singh, Jingjing Jiang, Silve Vicent

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

Original language	English (US)
Pages (from-to)	1218-1234.e7
Journal	Cancer cell
Volume	44
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2026.03.020
State	Published - Jun 8 2026

Keywords

KRAS oncogene
RAS(ON) multi-selective inhibitor
biliary tract cancer
cholangiocarcinoma
drug combinations
preclinical models
targeted therapy
therapy resistance

ASJC Scopus subject areas

Oncology
Cancer Research

Access to Document

10.1016/j.ccell.2026.03.020

Cite this

Entrialgo-Cadierno, R., Morali, K., Feliu, I., Wang, Y., Evans, J. W., Yañez-Bartolome, M., Lopez, I., Macaya, I., Cueto-Ureña, C., Sin-Coscujuela, D., Senent, Y., Herranz, J. M., Raghulan, R., Vaquero, J., Banales, J. M., Macarulla, T., Ponz-Sarvise, M., Pechuan-Jorge, X., Guruceaga, E., ... Vicent, S. (2026). Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma. Cancer cell, 44(6), 1218-1234.e7. https://doi.org/10.1016/j.ccell.2026.03.020

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 2026, 'Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma', Cancer cell, vol. 44, no. 6, pp. 1218-1234.e7. https://doi.org/10.1016/j.ccell.2026.03.020

@article{7bfc39532ee9438e80f3266414a059ee,

title = "Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma",

abstract = "About 25\% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.",

keywords = "KRAS oncogene, RAS(ON) multi-selective inhibitor, biliary tract cancer, cholangiocarcinoma, drug combinations, preclinical models, targeted therapy, therapy resistance",

author = "Rodrigo Entrialgo-Cadierno and Konstantina Morali and Iker Feliu and Yingyun Wang and Evans, \{James W.\} and Mariana Ya{\~n}ez-Bartolome and Ines Lopez and Irati Macaya and Cristina Cueto-Ure{\~n}a and Daniel Sin-Coscujuela and Yaiza Senent and Herranz, \{Jose M.\} and Rashi Raghulan and Javier Vaquero and Banales, \{Jesus M.\} and Teresa Macarulla and Mariano Ponz-Sarvise and Ximo Pechuan-Jorge and Elisabeth Guruceaga and Alyssa Schumpp and Garcia, \{Alia V.\} and Alyssa Kim and Herzberg, \{Benjamin O.\} and Nilofer Azad and Aparna Hegde and Tian, \{Tian V.\} and Ida Aronchik and Mallika Singh and Jingjing Jiang and Silve Vicent",

note = "Publisher Copyright: {\textcopyright} 2026 The Author(s)",

year = "2026",

month = jun,

day = "8",

doi = "10.1016/j.ccell.2026.03.020",

language = "English (US)",

volume = "44",

pages = "1218--1234.e7",

journal = "Cancer cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

AU - Entrialgo-Cadierno, Rodrigo

AU - Morali, Konstantina

AU - Feliu, Iker

AU - Wang, Yingyun

AU - Evans, James W.

AU - Yañez-Bartolome, Mariana

AU - Lopez, Ines

AU - Macaya, Irati

AU - Cueto-Ureña, Cristina

AU - Sin-Coscujuela, Daniel

AU - Senent, Yaiza

AU - Herranz, Jose M.

AU - Raghulan, Rashi

AU - Vaquero, Javier

AU - Banales, Jesus M.

AU - Macarulla, Teresa

AU - Ponz-Sarvise, Mariano

AU - Pechuan-Jorge, Ximo

AU - Guruceaga, Elisabeth

AU - Schumpp, Alyssa

AU - Garcia, Alia V.

AU - Kim, Alyssa

AU - Herzberg, Benjamin O.

AU - Azad, Nilofer

AU - Hegde, Aparna

AU - Tian, Tian V.

AU - Aronchik, Ida

AU - Singh, Mallika

AU - Jiang, Jingjing

AU - Vicent, Silve

PY - 2026/6/8

Y1 - 2026/6/8

N2 - About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

AB - About 25% of cholangiocarcinoma (CCA) tumors harbor KRAS mutations. Here, we investigated the activity of RAS(ON) multi-selective inhibitors, which target the active, GTP-bound state of mutant and wild-type variants of canonical RAS isoforms, in preclinical models and in patients with KRAS mutant CCA. RAS(ON) multi-selective inhibitors yield strong anticancer responses in cell- and patient-derived xenografts and immunocompetent allograft models. Consistent with these preclinical findings, we describe clinical activity of the RAS(ON) multi-selective inhibitor daraxonrasib in two patients with advanced KRAS G12 CCA. RAS-GTP inhibition also potentiates the activity of current standard-of-care CCA regimens to prolong survival in cell-derived human xenografts and mouse allografts. Furthermore, we demonstrate that intrinsic and acquired resistance to RAS(ON) multi-selective inhibitors mainly rely on mechanisms that drive RAS signaling overactivation. Overall, our findings indicate that KRAS mutant CCA is addicted to RAS signaling for proliferation and support the potential clinical evaluation of RAS-GTP inhibition in CCA.

KW - KRAS oncogene

KW - RAS(ON) multi-selective inhibitor

KW - biliary tract cancer

KW - cholangiocarcinoma

KW - drug combinations

KW - preclinical models

KW - targeted therapy

KW - therapy resistance

UR - https://www.scopus.com/pages/publications/105037369279

UR - https://www.scopus.com/pages/publications/105037369279#tab=citedBy

U2 - 10.1016/j.ccell.2026.03.020

DO - 10.1016/j.ccell.2026.03.020

M3 - Article

C2 - 42030930

AN - SCOPUS:105037369279

SN - 1535-6108

VL - 44

SP - 1218-1234.e7

JO - Cancer cell

JF - Cancer cell

IS - 6

ER -

Anticancer activity of RAS-GTP inhibition in cholangiocarcinoma

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this