Androgen deprivation–mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion
TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor-regulated (AR-regulated) TMPRSS2 expression. T:E fusion is associated with PTEN loss and is highly associated with decreased INPP4B expression, which together may compensate for ERG-mediated suppression of AKT signaling. We confirmed in PCa cells and a mouse PCa model that ERG suppresses IRS2 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 PTEN-intact and PTEN-deficient T:E fusion tumors, suggesting selection for a nonredundant function. As ERG in T:E fusion tumors is AR regulated, we further assessed whether AR inhibition increases AKT activity in T:E fusion tumors. A T:E fusion-positive 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 T:E fusion-positive versus -negative tumors. These findings indicate that AKT activation may mitigate the efficacy of AR-targeted therapy in T:E fusion PCa and that these patients may most benefit from combination therapy targeting AR and AKT.
Authors
- Mary‐Ellen Taplin (ORCID: https://orcid.org/0000-0002-3384-0300)
- Anson T. Ku (ORCID: https://orcid.org/0000-0002-6471-5502)
- David Johnson Einstein (ORCID: https://orcid.org/0000-0001-9163-3281)
- Fang Xie (ORCID: https://orcid.org/0000-0002-6121-0875)
- Olga Voznesensky (ORCID: https://orcid.org/0000-0003-1033-0938)
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Changmeng Cai (ORCID: https://orcid.org/0000-0002-8701-2586)
- Huihui Ye (ORCID: https://orcid.org/0000-0002-8307-9492)
- Seiji Arai (ORCID: https://orcid.org/0000-0002-9514-735X)
- Joshua W. Russo (ORCID: https://orcid.org/0000-0001-5481-0090)
- Fatima Karzai (ORCID: https://orcid.org/0000-0002-3244-1332)
- Carla Calagua (ORCID: https://orcid.org/0000-0003-4438-8046)
- Xin Yuan (ORCID: https://orcid.org/0000-0002-2558-0203)
- Larysa Poluben (ORCID: https://orcid.org/0000-0002-5433-6963)
- Luigi Giovanni Cecchi (ORCID: https://orcid.org/0009-0008-4362-9892)
- Alex Toker (ORCID: https://orcid.org/0000-0003-0723-4419)
- Steven P. Balk (ORCID: https://orcid.org/0000-0002-4546-7371)
- Betul Ersoy-Fazlioglu (ORCID: https://orcid.org/0000-0002-9410-3427)
- Sen Chen (ORCID: https://orcid.org/0000-0002-5872-2597)
- Fen Ma (ORCID: https://orcid.org/0000-0001-8297-7605)
- Seifeldin Awad
Institutions
- Beth Israel Deaconess Medical Center (US)
- Humanitas University (IT)
- Harvard University (US)
- University of Massachusetts Boston (US)
- Dana-Farber Cancer Institute (US)
- Dana-Farber/Harvard Cancer Center (US)
- National Cancer Institute (US)
- Gunma University Hospital (JP)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-10-02
- DOI
- https://doi.org/10.1172/jci192368
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- Prostate Cancer Foundation
- Astellas Pharma
- National Institutes of Health
- National Cancer Institute
- DOD Prostate Cancer Research Program