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We confirmed in PCa cells and a mouse PCa model that ERG suppresses\n                    <jats:italic>IRS2<\/jats:italic>\n                    and AKT activation. In contrast, ERG downregulation did not increase INPP4B, suggesting its decrease is indirect and reflects selective pressure to suppress INPP4B function. Notably, INPP4B expression was decreased in\n                    <jats:italic>PTEN<\/jats:italic>\n                    -intact and\n                    <jats:italic>PTEN<\/jats:italic>\n                    -deficient\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion tumors, suggesting selection for a nonredundant function. As ERG in\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion tumors. A\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion\u2013positive PDX had increased AKT activity in vivo and response to AKT inhibition in vitro after androgen deprivation. Moreover, two clinical trials of neoadjuvant AR inhibition prior to radical prostatectomy showed greater increases in AKT activation in the\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion\u2013positive versus \u2013negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR-targeted therapy in\n                    <jats:italic>T:E<\/jats:italic>\n                    fusion PCa and that these patients may most benefit from combination therapy targeting AR and AKT.\n                  <\/jats:p>","DOI":"10.1172\/jci192368","type":"journal-article","created":{"date-parts":[[2025,10,2]],"date-time":"2025-10-02T16:00:22Z","timestamp":1759420822000},"source":"Crossref","is-referenced-by-count":2,"title":["Androgen deprivation\u2013mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion"],"prefix":"10.1172","volume":"135","author":[{"given":"Fen","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Medicine and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 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