Androgen deprivation–mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion
Fen Ma, Sen Chen, Luigi Cecchi, Betul Ersoy-Fazlioglu, Joshua W. Russo, Seiji Arai, Seifeldin Awad, Carla Calagua, Fang Xie, Larysa Poluben, Olga Voznesensky, Anson T. Ku, Fatima Karzai, Changmeng Cai, David J. Einstein, Huihui Ye, Xin Yuan, Alex Toker, Mary-Ellen Taplin, Adam G. Sowalsky, Steven P. Balk
Fen Ma, Sen Chen, Luigi Cecchi, Betul Ersoy-Fazlioglu, Joshua W. Russo, Seiji Arai, Seifeldin Awad, Carla Calagua, Fang Xie, Larysa Poluben, Olga Voznesensky, Anson T. Ku, Fatima Karzai, Changmeng Cai, David J. Einstein, Huihui Ye, Xin Yuan, Alex Toker, Mary-Ellen Taplin, Adam G. Sowalsky, Steven P. Balk
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Research Article Cell biology Oncology

Androgen deprivation–mediated activation of AKT is enhanced in prostate cancer with TMPRSS2:ERG fusion

Abstract

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

Fen Ma, Sen Chen, Luigi Cecchi, Betul Ersoy-Fazlioglu, Joshua W. Russo, Seiji Arai, Seifeldin Awad, Carla Calagua, Fang Xie, Larysa Poluben, Olga Voznesensky, Anson T. Ku, Fatima Karzai, Changmeng Cai, David J. Einstein, Huihui Ye, Xin Yuan, Alex Toker, Mary-Ellen Taplin, Adam G. Sowalsky, Steven P. Balk

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Figure 5

Androgen deprivation increases AKT activity and dependence in T:E fusion–positive PDX.

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Androgen deprivation increases AKT activity and dependence in T:E fusion...
(A) T:E fusion–positive BIDPC4 PDXs were established in male scid mice as subcutaneous tumors. Mice were sacrificed prior to or at approximately 2 weeks after castration. FFPE sections were stained for ERG, pAKT(473), and pS6 as indicated, and representative slides are shown. Original magnification, ×10. (B) Cells from BIDPC4 PDX were cultured in medium with 10% FBS or in medium with 10% charcoal stripped FBS (CSS). Ipatasertib was then added at the indicated concentrations, and cell recovery was assessed by CellTiter-Glo luminescent cell viability assay after 7 days. Luminescent readouts were normalized to the average luminescent signal of DMSO under the respective conditions, with 6 replicates per dose of drug. Data are shown as mean ± SD. The graph illustrates the half-maximal inhibitory concentration (IC50) in the presence of FBS compared with CCS. Nonlinear regression curves were generated by a variable slope model. (C) Responses to MK2206 were assayed as in B.