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. 2025 Oct 11.
doi: 10.1038/s41416-025-03216-w. Online ahead of print.

Modeling response to the KRAS-G12C inhibitor AZD4625 in KRASG12C NSCLC patient-derived xenografts reveals insights into primary resistance mechanisms

Joshua C Rosen  1   2 , Pinjiang Cao  1 , Nhu-An Pham  1 , Matthew Waas  1 , Quan Li  1 , Katrina Hueniken  1   3 , Mutian Wang  1 , Roya Navab  1 , Leanne Wybenga-Groot  4   5 , Nikolina Radulovich  1 , Michael Niedbala  6 , Alex Koers  7 , Sarah Ross  7 , Michael F Moran  4   5   8 , Adrian Sacher  9   10 , Ming-Sound Tsao  11   12   13
Affiliations

Modeling response to the KRAS-G12C inhibitor AZD4625 in KRASG12C NSCLC patient-derived xenografts reveals insights into primary resistance mechanisms

Joshua C Rosen et al. Br J Cancer. .

Abstract

Background: KRASG12C alterations are present in ~13% of lung adenocarcinomas. AZD4625 is a covalent small molecule inhibitor that selectively binds and inhibits GDP-KRASG12C, leading to reduced cell viability and protein signaling responsible for tumor survival in models with this gain-of-function alteration.

Methods: We studied short-term changes in signaling and mechanisms of primary resistance to AZD4625 in twelve KRASG12C lung adenocarcinoma patient-derived xenografts (PDX) and six organoids derived from these twelve models.

Results: Sustained tumor regression in four (33%) PDXs was observed while the remaining eight models were intrinsically resistant to AZD4625. Organoid responses to AZD4625 were concordant with their derived PDXs. Acute AZD4625 exposure significantly decreased gene expression of the ERK1/2 negative regulator, DUSP6, in all models while protein MAPK and AKT/mTOR signals were downregulated more frequently in the AZD4625-sensitive than AZD4625-resistant cohorts. Analyzing PDX transcriptomes and proteomes identified mTOR signaling as a putative mechanism of primary resistance to AZD4625.

Conclusions: Our findings confirm AZD4625 as a highly active KRASG12C inhibitor. This data also supports the use of PDX models in understanding resistance mechanisms that may be leveraged to develop more active combination therapies.

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Conflict of interest statement

Competing interests: MN, AK and SR are AstraZeneca employees and shareholders. Dr. Sacher declares institutional Research & Clinical Trial PI from AstraZeneca, Amgen, Genentech, Merck, Lilly, Pfizer, BMS, Spectrum, GSK, Iovance, CRISPR Therapeutics, BridgeBio, HotSpot Therapeutics, AdaptImmune; Advisory committee (no personal fees): Genentech, Amgen, Merck; Travel expenses for clinical trial investigator meetings: Amgen, Merck, Genentech-Roche. MST received research grant (to institution) from AstraZeneca and Sanofi, and consultancy honoraria from AstraZeneca, Daiichi-Sankyo, Abbvie, Boehringer-Ingelheim and Sanofi. All other authors have nothing to declare. Ethics approval: Study protocols were approved by the Research Ethics Board (REB 09-0510-T) and Animal Care Committee (AUP#743) in accordance to ARRIVE guidelines at the University Health Network. This study was performed in accordance with the ethical principles outlines in the Declaration of Helsinki.

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