Small-Molecule Activators of Protein Phosphatase 2A for the Treatment of Castration-Resistant Prostate Cancer
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 12, 2018
- Source ID
- 10.1158/0008-5472.can-17-0123
Entities
People
- Abbey Perl
- Agnes Stachnik
- Alexander Kirschenbaum
- Alice C. Levine
- Analisa DiFeo
- Cynthia C.T. Sprenger
- Danica Wiredja
- Daniel Mcquaid
- Daniela Schlatzer
- David B. Kastrinsky
- David Callejas
- David L. Brautigan
- Divya Hoon
- Goutham Narla
- Janna Kiselar
- Jaya Sangodkar
- John P. Sfakianos
- Kimberly Mcclinch
- Matthew D. Galsky
- Maxwell Cooper
- Michael Ohlmeyer
- Nilesh Zaware
- Rita A. Avelar
- Rosalie C Sears
- Shen Yao
- Stephen R Plymate
- Sudeh Izadmehr
- William K. Oh
- Yiannis Ioannou
- Yixuan Gong
Organizations
- Case Western Reserve University
- Icahn School of Medicine at Mount Sinai
- National Cancer Institute
- Oregon Health & Science University
- Prostate Cancer Foundation
- United States Department of Defense
- University of Virginia
- University of Washington