{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:16:39Z","timestamp":1788412599988,"version":"build-2803163510"},"reference-count":38,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006827","name":"Florida Department of Health","doi-asserted-by":"publisher","award":["23B13"],"award-info":[{"award-number":["23B13"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"publisher"}]},{"award":["23B13"],"award-info":[{"award-number":["23B13"]}],"id":[{"id":"https:\/\/ror.org\/03e1xkn26","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive adaptive signaling plasticity and metabolic reprogramming that contribute to therapeutic resistance. While the PI3K\u2013mTOR pathway is a central regulator of these processes, the role of the FGF19\u2013FGFR4 axis and its interaction with PI3K-mTOR signaling remains incompletely defined in PDAC. This study investigated whether co-targeting FGFR4 and PI3K-mTOR signaling could overcome adaptive pathway reactivation and suppress tumor-promoting phenotypes. PDAC cell lines representing a spectrum of FGFR4 dependence were treated with the selective FGFR4 inhibitor fisogatinib in combination with the clinically relevant PI3K\u2013mTOR inhibitor gedatolisib. Transcriptomic analyses of TCGA data, along with molecular and functional responses, were evaluated. Transcriptomic analysis demonstrated a positive association between FGFR4 and PI3K\u2013mTOR signaling and linked combined pathway components with poorer overall survival. Across heterogeneous PDAC models, combined inhibition reduced viability, clonogenic survival, migration, and cell-cycle progression more consistently than monotherapy. Apoptosis induction was driven principally by fisogatinib and combination treatment, resulting in comparable apoptotic responses across cell lines. Mechanistically, combined inhibition converged on increased 4E-BP1 inhibitory activity, despite compensatory ERK-RSK pathway activation, indicating that adaptive MAPK was insufficient to restore downstream translational output. In FGFR4-dependent cells, the combined inhibition also reduced secretion of the FGFR4 ligand FGF19. The FGFR4 and PI3K\u2013mTOR signaling comprises a partially interconnected network in PDAC that converges on 4E-BP1-dependent translational control. Dual pathway inhibition consistently and additively suppressed tumor-associated phenotypes despite compensatory MAPK activation, with the clearest added benefit over fisogatinib alone in migration, cell-cycle control, and 4E-BP1 modulation, supporting translational regulation as a shared therapeutic vulnerability. These findings provide a preliminary rationale for biomarker-guided strategies targeting FGFR4 and PI3K\u2013mTOR signaling in pancreatic cancer.<\/jats:p>","DOI":"10.3390\/ijms27177722","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dual Targeting of FGFR4 and PI3K\u2013mTOR Suppresses Tumor-Associated Phenotypes in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4086-0151","authenticated-orcid":false,"given":"Joseph A.","family":"Goode","sequence":"first","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savannah A.","family":"Harris","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7014-0397","authenticated-orcid":false,"given":"Deborah A.","family":"Altomare","sequence":"additional","affiliation":[{"name":"Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32827, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. 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