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Adv."],"published-print":{"date-parts":[[2026,5,1]]},"abstract":"<jats:p>\n                    Cancer therapeutics frequently fail in clinical trials because of poor therapeutic index (efficacy-to-toxicity ratio). We systematically identified targets likely to have a good therapeutic index, revealing insulin receptor substrate 4 (IRS4) as a dependency in\n                    <jats:italic toggle=\"yes\">IRS4<\/jats:italic>\n                    -expressing cancers. Pan-cancer analysis of pediatric-enriched cancers revealed\n                    <jats:italic toggle=\"yes\">IRS4<\/jats:italic>\n                    expression consistent with dependency in 68% of choroid plexus, 37% of malignant rhabdoid, 31% of NUT midline, and 5% of osteosarcomas, while in adult cancers, it was expressed in 8% of uterine leiomyosarcomas and 1 to 2% of lung squamous, stomach, and breast carcinomas.\n                    <jats:italic toggle=\"yes\">IRS4<\/jats:italic>\n                    expression in adult tumors was associated with enhancer hijacking rearrangements, including recurrent\n                    <jats:italic toggle=\"yes\">GATA3-IRS4<\/jats:italic>\n                    and\n                    <jats:italic toggle=\"yes\">ANKRD30A-IRS4<\/jats:italic>\n                    in breast cancer, while rhabdoid and NUT midline cancers expressed\n                    <jats:italic toggle=\"yes\">IRS4<\/jats:italic>\n                    epigenetically. IRS4 fueled cancer dependency through PI3K-Akt activation, and domain analysis revealed the PH and PTB domains, which have a predicted drug pocket, to be dispensable, suggesting degradation-based modalities. These data reveal IRS4 as a target in IRS4-expressing cancers and suggest inhibitory approaches.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb3503","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T17:58:27Z","timestamp":1777485507000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":2,"title":["IRS4 is a PI3K-activating cancer dependency up-regulated through DNA rearrangements or epigenetic mechanisms in multiple solid tumors"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6680-2688","authenticated-orcid":true,"given":"Khadija","family":"Banu","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children\u2019s Research Hospital, Memphis, TN, 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