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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (20)
Erika Testa
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Clara Dezi
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Francesca Lovat
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University
Geny Piro
Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico
Carmine Carbone
Marina Capece
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University
Giovanni Nigita
Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University
Erisa Putro
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Elisabetta Di Renzi
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Alessandra Simeone
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Luca Reggiani Bonetti
Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia
Roberto Cirombella
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Paolo Magistri
Surgical, Medical and Dental Department of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia
Vincenzo Corbo
Davide Pasini
Barbara Belletti
Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute
Gustavo Baldassarre
Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute
Andrea Vecchione
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome
Carlo M. Croce
Department of Cancer Biology and Genetics, Wexner Medical Center, College of Medicine, The Ohio State University Comprehensive Cancer Center
Gian Luca Rampioni Vinciguerra
Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome