{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:41:11Z","timestamp":1785426071478,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wall Fund for Pancreatic Cancer Research at City of Hope","award":["50393"],"award-info":[{"award-number":["50393"]}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U2C CA252971"],"award-info":[{"award-number":["U2C CA252971"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30 CA033572"],"award-info":[{"award-number":["P30 CA033572"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["U54 CA285116"],"award-info":[{"award-number":["U54 CA285116"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"award":["U2C CA252971"],"award-info":[{"award-number":["U2C CA252971"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 CA033572"],"award-info":[{"award-number":["P30 CA033572"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54 CA285116"],"award-info":[{"award-number":["U54 CA285116"]}],"id":[{"id":"https:\/\/ror.org\/02t771148","id-type":"ROR","asserted-by":"publisher"}]},{"name":"City of Hope Cancer Control and Population Sciences Program"},{"name":"Drug Development and Capacity Building: A UCR\/CoH-CCC Partnership project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy marked by substantial molecular heterogeneity and variable response to gemcitabine-based therapy. While KRAS mutations are nearly universal, the broader RTK-RAS and MAPK signaling architecture and its relationship to treatment response remain incompletely defined. We conducted an integrative clinical-genomic analysis of 184 PDAC tumors stratified by age at diagnosis and gemcitabine exposure, interrogating somatic alterations across curated RTK-RAS\/MAPK gene sets. Conversational artificial intelligence agents (AI-HOPE-RTK-RAS and AI-HOPE-MAPK) enabled dynamic cohort construction and pathway-level analyses, with findings validated using standard statistical methods. In late-onset PDAC, ERBB2 and RET mutations were significantly enriched in gemcitabine-treated tumors. Early-onset cases demonstrated differential enrichment of CACNA2D family alterations in non-treated tumors and higher frequencies of FLNB and TP53 mutations in treated disease. Importantly, late-onset patients not treated with gemcitabine who lacked RTK-RAS or MAPK alterations exhibited significantly improved overall survival. These findings reveal age- and treatment-dependent pathway dependencies beyond canonical KRAS status and support a precision oncology framework in PDAC. Conversational AI facilitated rapid, multidimensional clinical\u2013genomic integration to uncover clinically relevant signaling substructures.<\/jats:p>","DOI":"10.3390\/ijms27073011","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:48:41Z","timestamp":1774532921000},"page":"3011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Deciphering RTK-RAS and MAPK Pathway Dependencies in Gemcitabine-Treated Pancreatic Ductal Adenocarcinoma Through Conversational Artificial Intelligence"],"prefix":"10.3390","volume":"27","author":[{"given":"Fernando C.","family":"Diaz","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5991-9779","authenticated-orcid":false,"given":"Brigette","family":"Waldrup","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1789-4197","authenticated-orcid":false,"given":"Francisco G.","family":"Carranza","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Manjarrez","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-6414","authenticated-orcid":false,"given":"Enrique","family":"Velazquez-Villarreal","sequence":"additional","affiliation":[{"name":"Department of Integrative Translational Sciences, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA"},{"name":"City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e171","DOI":"10.1097\/MPA.0000000000002408","article-title":"Somatic Genomic Profiling of Pancreatic Ductal Adenocarcinomas From a Diverse Cohort of Patients","volume":"54","author":"Riner","year":"2025","journal-title":"Pancreas"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Monge, C., Waldrup, B., Carranza, F.G., Manjarrez, S., and Velazquez-Villarreal, E. 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