Advertisement

ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI192368

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

Fen Ma,1 Sen Chen,1 Luigi Cecchi,1 Betul Ersoy-Fazlioglu,1 Joshua W. Russo,1 Seiji Arai,1 Seifeldin Awad,1 Carla Calagua,1 Fang Xie,1 Larysa Poluben,1 Olga Voznesensky,1 Anson T. Ku,2 Fatima Karzai,2 Changmeng Cai,1 David J. Einstein,1 Huihui Ye,1 Xin Yuan,1 Alex Toker,3 Mary-Ellen Taplin,4 Adam G. Sowalsky,3 and Steven P. Balk1

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Ma, F. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Chen, S. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Cecchi, L. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Ersoy-Fazlioglu, B. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Russo, J. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Arai, S. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Awad, S. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Calagua, C. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Xie, F. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Poluben, L. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Voznesensky, O. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Ku, A. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Karzai, F. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Cai, C. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Einstein, D. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Ye, H. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Yuan, X. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Toker, A. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Taplin, M. in: PubMed | Google Scholar

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Sowalsky, A. in: PubMed | Google Scholar |

1Department of Medicine and Cancer Center, Harvard Medical School, Boston, United States of America

2Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

3Department of Pathology and Cancer Center, Harvard Medical School, Boston, United States of America

4Department of Medical Oncology, Harvard Medical School, Boston, United States of America

Find articles by Balk, S. in: PubMed | Google Scholar

Published October 2, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI192368.
Copyright © 2025, Ma et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published October 2, 2025 - Version history
View PDF
Abstract

TMPRSS2:ERG gene fusion (T:E fusion) in prostate adenocarcinoma (PCa) puts ERG under androgen receptor (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 is 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.

Graphical Abstract
graphical abstract
Supplemental material

View Unedited blot and gel images

View

Version history
  • Version 1 (October 2, 2025): In-Press Preview
Advertisement
Advertisement