Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma.

Abstract

KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), driving tumor initiation and progression in the vast majority of cases, with KRAS^G12D 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 KRAS^G12D 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.