Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma
Menée à l'aide de lignées cellulaires, de xénogreffes, d'organoïdes et de tissus pancréatiques prélevés sur des patients atteints d'un adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel une surexpression de la protéine Fra-2, un médiateur de la réponse au stress, favorise la résistance des cellules cancéreuses à l'inhibiteur de KRAS MRTX-1133 via l'augmentation de l'expression de mTOR
KRAS mutations are present in the majority of pancreatic ductal adenocarcinomas (PDAC) and are key drivers of tumor progression. Although mutation-specific KRAS inhibitors (KRASi) have shown encouraging clinical activity, their therapeutic benefit is limited by the insurgence of resistance. Here, we hypothesized that the stress-response mediator Fra-2 contributes to this resistance. We show that treatment with the KRASi MRTX-1133 induces Fra-2 overexpression, leading to transcriptional rewiring that includes regulation of mTOR expression. Importantly, combination therapy targeting Fra-2 significantly improves the efficacy of KRASi. These findings provide mechanistic insight into the recurrent activation of the mTOR pathway in MRTX-1133–resistant PDAC and identify Fra-2 as a promising therapeutic target for combination strategies. KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), driving tumor initiation and progression in the vast majority of cases, with KRASG12D being the most prevalent variant. Recent advances have led to the development of mutation-specific KRAS inhibitors (KRASi), yet their clinical impact is hindered by the rapid onset of drug resistance. In this study, we identify Fos-related antigen-2 (Fra-2), a stress-responsive transcription factor of the AP-1 family, as a key mediator of adaptive resistance to the KRASG12D selective inhibitor MRTX-1133. Using a combination of established PDAC cell lines, xenograft models, and patient-derived organoids, we demonstrate that Fra-2 expression is consistently upregulated following MRTX-1133 treatment. Functional assays reveal that Fra-2 overexpression promotes resistance by reprogramming the transcriptional landscape, directly enhancing mTOR expression and signaling. Consistently, FRA2 and MTOR levels strongly correlate in PDAC patient samples. Collectively, these findings uncover a mechanistic interplay between Fra-2 and the mTOR pathway in MRTX-1133-resistant PDAC, highlighting that targeting Fra-2 may represent a valuable approach to enhance the efficacy of KRASi.
Proceedings of the National Academy of Sciences , article en libre accès, 2026