Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer
19 affiliations
- 1Revolution Medicines, Redwood City, CA, USA
- 2Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
- 3Broad Institute of MIT and Harvard, Cambridge, MA, USA
- 4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- 5Harvard Medical School, Boston, MA, USA
- 6The Christ Hospital Health Network, Parkview Physician Group - Parkview Cancer Institute, Cincinnati, OH, USA
- 7NEXT Oncology Virginia, Virginia Cancer Specialists Research Institute, Fairfax, VA, USA
- 8Memorial Sloan Kettering Cancer Center, David M. Rubenstein Center for Pancreatic Cancer Research, Weill Cornell Medical College, New York, NY, USA
- 9The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA
- 10University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA
- 11Mary Crowley Cancer Research, Texas Oncology, Dallas, TX, USA
- 12Sarah Cannon Research Institute, Nashville, TN, USA
- 13NEXT Oncology, San Antonio, TX, USA
- 14NYU Langone Health, Perlmutter Cancer Center, New York, NY, USA
- 15Revolution Medicines, Redwood City, CA, USA. [email protected]
- 16Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
- 17Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected]
- 18Harvard Medical School, Boston, MA, USA. [email protected]
- 19Revolution Medicines, Redwood City, CA, USA. [email protected]
Abstract
Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.
Related
- Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer
- Efficacy and Safety of Daraxonrasib (RMC-6236) in Previously Treated Metastatic RAS-Mutated Pancreatic Ductal Adenocarcinoma: A Systematic Review.
- CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC
- Cost-Effectiveness of Daraxonrasib vs Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma
- 174 TEM8-driven SynNotch CAR-T cells enable tumor-selective targeting of pancreatic cancer
BibTeX
@article{aronchik2026acquired,
title = {{Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer}},
author = {Ida Aronchik and Sumit Kar and Yongxian Zhuang and Ethan Ahler and Lo Lai and Vidya Seshadri and Yu Chi Yang and Ashenafi Shiferaw Bulle and Marie Ménard and Biswadeep Nayak and Mark P. Labrecque and Julien Dilly and Eejung Kim and Lingyan Jiang and Jason K. Yano and Urszula N. Wasko and Ciara Helland and Sean Bredeson and Brett Garrick and Yevgeniy Gindin and Brad Sickler and Xing Wei and Kyle J. Seamon and Jingjing Jiang and Kian‐Huat Lim and Matthew T. Holderfield and Elsa Quintana and Aparna Hegde and Zeena Salman and Alexander Starodub and Alexander I. Spira and Wungki Park and David S. Hong and Minal A. Barve and Meredith S. Pelster and David Sommerhalder and Salman Rafi Punekar and Ignacio Garrido‐Laguna and Brian Matthew Wolpin and Anirban Maitra and William Clay Gustafson and Steve M. Kelsey and Jacqueline A.M. Smith and Kevin K. Lin and Andrew J. Aguirre and Mallika Singh},
journal = {Nature Medicine},
year = {2026},
month = aug,
doi = {10.1038/s41591-026-04537-w},
url = {https://doi.org/10.1038/s41591-026-04537-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer
AU - Ida Aronchik
AU - Sumit Kar
AU - Yongxian Zhuang
AU - Ethan Ahler
AU - Lo Lai
AU - Vidya Seshadri
AU - Yu Chi Yang
AU - Ashenafi Shiferaw Bulle
AU - Marie Ménard
AU - Biswadeep Nayak
AU - Mark P. Labrecque
AU - Julien Dilly
AU - Eejung Kim
AU - Lingyan Jiang
AU - Jason K. Yano
AU - Urszula N. Wasko
AU - Ciara Helland
AU - Sean Bredeson
AU - Brett Garrick
AU - Yevgeniy Gindin
AU - Brad Sickler
AU - Xing Wei
AU - Kyle J. Seamon
AU - Jingjing Jiang
AU - Kian‐Huat Lim
AU - Matthew T. Holderfield
AU - Elsa Quintana
AU - Aparna Hegde
AU - Zeena Salman
AU - Alexander Starodub
AU - Alexander I. Spira
AU - Wungki Park
AU - David S. Hong
AU - Minal A. Barve
AU - Meredith S. Pelster
AU - David Sommerhalder
AU - Salman Rafi Punekar
AU - Ignacio Garrido‐Laguna
AU - Brian Matthew Wolpin
AU - Anirban Maitra
AU - William Clay Gustafson
AU - Steve M. Kelsey
AU - Jacqueline A.M. Smith
AU - Kevin K. Lin
AU - Andrew J. Aguirre
AU - Mallika Singh
PY - 2026
DA - 2026/08/01
JO - Nature Medicine
DO - 10.1038/s41591-026-04537-w
UR - https://doi.org/10.1038/s41591-026-04537-w
AB - Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.
SN - 1078-8956
SN - 1546-170X
SN - 1744-7933
ER -