Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.
СтатьяКлиническое исследование II фазыКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Aronchik Ida, Kar Sumit, Zhuang Yongxian, Ahler Ethan, Lai Lick Pui, Seshadri Vidya, Yang Yu Chi, Bulle Ashenafi, Menard Marie, Nayak Biswadeep, Labrecque Mark P, Dilly Julien, Kim Eejung, Jiang Lingyan, Yano Jason, Wasko Urszula N, Helland Ciara, Bredeson Sean, Garrick Brett, Gindin Yevgeniy, Sickler Brad, Wei Xing, Seamon Kyle, Jiang Jingjing, Lim Kian-Huat, Holderfield Matthew, Quintana Elsa, Hegde Aparna, Salman Zeena, Starodub Alexander, Spira Alexander, Park Wungki, Hong David S, Barve Minal, Pelster Meredith, Sommerhalder David, Punekar Salman R, Garrido-Laguna Ignacio, Wolpin Brian M, Maitra Anirban, Gustafson W Clay, Kelsey Steve, Smith Jacqueline A M, Lin Kevin K, Aguirre Andrew J, Singh Mallika
Аннотация
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.