Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer

Kimberly McClinch, Rita A. Avelar, David Callejas, Sudeh Izadmehr, Danica Wiredja, Abbey Perl, Jaya Sangodkar, David B. Kastrinsky, Daniela Schlatzer, Maxwell Cooper, Janna Kiselar, Agnes Stachnik, Shen Yao, Divya Hoon, Daniel McQuaid, Nilesh Zaware, Yixuan Gong, David L. Brautigan, Stephen R. Plymate, Cynthia C.T. SprengerWilliam K. Oh, Alice C. Levine, Alexander Kirschenbaum, John P. Sfakianos, Rosalie Sears, Analisa DiFeo, Yiannis Ioannou, Michael Ohlmeyer, Goutham Narla, Matthew D. Galsky

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Primary prostate cancer is generally treatable by androgen deprivation therapy, however, later recurrences of castrate-resistant prostate cancer (CRPC) that are more difficult to treat nearly always occur due to aberrant reactivation of the androgen receptor (AR). In this study, we report that CRPC cells are particularly sensitive to the growth-inhibitory effects of reengineered tricyclic sulfonamides, a class of molecules that activate the protein phosphatase PP2A, which inhibits multiple oncogenic signaling pathways. Treatment of CRPC cells with small-molecule activators of PP2A (SMAP) in vitro decreased cellular viability and clonogenicity and induced apoptosis. SMAP treatment also induced an array of significant changes in the phosphoproteome, including most notably dephosphorylation of full-length and truncated isoforms of the AR and downregulation of its regulatory kinases in a dose-dependent and time-dependent manner. In murine xenograft models of human CRPC, the potent compound SMAP-2 exhibited efficacy comparable with enzalutamide in inhibiting tumor formation. Overall, our results provide a preclinical proof of concept for the efficacy of SMAP in AR degradation and CRPC treatment. Significance: A novel class of small-molecule activators of the tumor suppressor PP2A, a serine/threonine phosphatase that inhibits many oncogenic signaling pathways, is shown to deregulate the phosphoproteome and to destabilize the androgen receptor in advanced prostate cancer. Cancer Res; 78(8); 2065–80. 2018 AACR.

Original languageEnglish (US)
Pages (from-to)2065-2080
Number of pages16
JournalCancer Research
Volume78
Issue number8
DOIs
StatePublished - Apr 15 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    McClinch, K., Avelar, R. A., Callejas, D., Izadmehr, S., Wiredja, D., Perl, A., Sangodkar, J., Kastrinsky, D. B., Schlatzer, D., Cooper, M., Kiselar, J., Stachnik, A., Yao, S., Hoon, D., McQuaid, D., Zaware, N., Gong, Y., Brautigan, D. L., Plymate, S. R., ... Galsky, M. D. (2018). Small-molecule activators of protein phosphatas 2A for the treatment of castration-resistant prostate cancer. Cancer Research, 78(8), 2065-2080. https://doi.org/10.1158/0008-5472.CAN-17-0123