Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer

作者：Ida Aronchik, Sumit Kar, Yongxian Zhuang, Ethan Ahler, Lo Lai, Vidya Seshadri, Yu Chi Yang, Ashenafi Bulle, Marie Ménard, Biswadeep Nayak, Mark P. Labrecque, Julien Dilly, Eejung Kim, Lingyan Jiang, Jason Yano, Urszula N. Wasko, Ciara Helland, Sean Bredeson, Brett Garrick, Yevgeniy Gindin, Brad Sickler, Xing Wei, Kyle Seamon, Jingjing Jiang, Kian‐Huat Lim, Matthew Holderfield, Elsa Quintana, Aparna Hegde, Zeena Salman, Alexander Starodub, Alexander Spira, Wungki Park, David S. Hong, Minal Barve, Meredith Pelster, David Sommerhalder, Salman R. Punekar, Ignacio Garrido-Laguna, Brian M. Wolpin, Anirban Maitra, W. Clay Gustafson, Steve Kelsey, Jacqueline A.M. Smith, Kevin K. Lin, Andrew J. Aguirre, Mallika Singh · 发表于：Nature Medicine · 年份：2026 · DOI：10.1038/s41591-026-04537-w · 被引用次数：3 · 研究领域：Pancreatic and Hepatic Oncology Research、Pancreatitis Pathology and Treatment、Lung Cancer Treatments and Mutations

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 gu...