Efrosini Tsouko, Ali Shojaie, Ayesha S. Khan, David A. Bader, Harene Venghatakrishnan, Dean P. Edwards, Ganesh S. Palapattu, Daniel E. Frigo, Vihas T. Vasu, Sean E. McGuire, Rajni Sonavane, Lawrence Chan, Yiqing Zhang, Alexander Zaslavsky, Fabio Stossi, Nagireddy Putluri, Katrin Panzitt, Mohan Manikkam, Nancy L. Weigel, Akash K. Kaushik, Michael Ittmann, Arun Sreekumar, Adam T. Szafran, Nicholas Mitsiades, Stacy M. Lloyd, Xuhong Cao, Benny Abraham Kaipparettu, Arul M. Chinnaiyan, Michael A. Mancini, Subhamoy Dasgupta, Susmita Samanta, Vasanta Putluri, Shixia Huang, George Michailidis, Hangwen Li, and Rohit Mehra
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal studies, while also demonstrates additive efficacy when combined with enzalutamide in-vitro. These observations demonstrate the therapeutic value of targeting HBP in CRPC., The molecular alterations driving anti-androgen resistance in prostate cancer are unclear. Here, the authors show, using a network-based approach, that inhibition of the hexosamine biosynthetic pathway is necessary to develop resistance and that increasing the activity of the pathway enhances the anti-androgen response.