{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:22:42Z","timestamp":1785435762388,"version":"3.56.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["30656"],"award-info":[{"award-number":["30656"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["28801"],"award-info":[{"award-number":["28801"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:p>\n                    KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), driving tumor initiation and progression in the vast majority of cases, with KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    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\n                    <jats:sup>G12D<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2601788123","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:37:36Z","timestamp":1777484256000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma"],"prefix":"10.1073","volume":"123","author":[{"given":"Erika","family":"Testa","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dezi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Lovat","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geny","family":"Piro","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Carbone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario Agostino Gemelli Istituto di Ricovero e Cura a Carattere Scientifico","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Capece","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Nigita","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erisa","family":"Putro","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta Di","family":"Renzi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Simeone","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca Reggiani","family":"Bonetti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02d4c4y02","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia","place":["Modena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Cirombella","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Magistri","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02d4c4y02","id-type":"ROR","asserted-by":"publisher"}],"name":"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","place":["Modena, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Corbo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039bp8j42","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Engineering for Innovation Medicine, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Pasini","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/039bp8j42","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Engineering for Innovation Medicine, University of Verona","place":["Verona, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2249-0285","authenticated-orcid":false,"given":"Barbara","family":"Belletti","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tfzc498","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute","place":["Aviano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-8825","authenticated-orcid":false,"given":"Gustavo","family":"Baldassarre","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04tfzc498","id-type":"ROR","asserted-by":"publisher"}],"name":"Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, National Cancer Institute","place":["Aviano, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vecchione","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-1457","authenticated-orcid":false,"given":"Carlo M.","family":"Croce","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Luca","family":"Rampioni Vinciguerra","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02be6w209","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, Sapienza University of Rome","place":["Rome, Italy"]},{"name":"Department of Cancer Biology and Genetics and Comprehensive Cancer Center, The Ohio State University","place":["Columbus"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.13027"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2024.53588"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-018-0112-1"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.08.009"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1903387"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1200\/OP.22.00328"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00780-4"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1694-1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2103695"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.13168"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.1c01688"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02007-7"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0177"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1209"},{"key":"e_1_3_4_15_2","article-title":"Role of Fra-2 in cancer","volume":"31","author":"Rampioni Vinciguerra G. L.","year":"2023","unstructured":"G. L. Rampioni Vinciguerra , Role of Fra-2 in cancer. Cell Death Differ. 31, 149 (2023), 10.1038\/s41418-023-01248-4.","journal-title":"Cell Death Differ."},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2404188121"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.27235"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01740-4"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.05.007"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-022-01228-z"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02796382"},{"key":"e_1_3_4_22_2","unstructured":"G. L. Rampioni Vinciguerra G. Nigita Data From \u201cFra2 role in PDAC response under MRTX-1133 treatment\u201d. GEO. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE318496. Deposited 13 April 2026."},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/database\/baw100"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.02686"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24119313"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-023-02313-y"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-020-00904-3"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2024.11.009"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20201414"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50063-z"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.07.002"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-1066"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18762-5"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17289-y"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08721-9"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2004088"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3398"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2601788123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:38:27Z","timestamp":1777484307000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2601788123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,29]]},"references-count":39,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,5,5]]}},"alternative-id":["10.1073\/pnas.2601788123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2601788123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,29]]},"assertion":[{"value":"2026-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2601788123"}}