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

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

  • Proc Natl Acad Sci U S A. 2026 May 5;123(18):e2601788123. doi: 10.1073/pnas.2601788123.
Erika Testa # 1,  Clara Dezi # 1,  Francesca Lovat 2,  Geny Piro 3,  Carmine Carbone 3,  Marina Capece 2,  Giovanni Nigita 2,  Erisa Putro 1,  Elisabetta Di Renzi 1,  Alessandra Simeone 1,  Luca Reggiani Bonetti 4,  Roberto Cirombella 1,  Paolo Magistri 5,  Vincenzo Corbo 6,  Davide Pasini 6,  Barbara Belletti 7,  Gustavo Baldassarre 7,  Andrea Vecchione 1,  Carlo M Croce # 2,  Gian Luca Rampioni Vinciguerra # 1 2
Affiliations

Affiliations

  • 1 Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome, Rome 00189, Italy.
  • 2 Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210.
  • 3 Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Rome 00136, Italy.
  • 4 Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena 41100, Italy.
  • 5 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, Modena 41100, Italy.
  • 6 Department of Engineering for Innovation Medicine, University of Verona, Verona 37134, Italy.
  • 7 Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute, Aviano 33081, Italy.
  • # Contributed equally.
PMID: 42054368 DOI: 10.1073/pnas.2601788123
Abstract

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.

Keywords

Fra-2; KRAS inhibitors; MRTX-1133; mTOR pathway; pancreatic cancer.

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