Men with advanced prostate cancer are typically treated with androgen deprivation therapy, but most ultimately develop resistance and incurable disease (e.g. castration-resistant prostate cancer (CRPC)). The majority of CRPCs overexpress the epigenetic enzyme EZH2 and harbor alterations in the PI3K pathway, providing two targetable pathways outside of AR. Here we show that EZH2 inhibitors synergize with PI3K, AKT, or mTORC1 inhibitors to kill CRPC in vitro and promote tumor regression in vivo. Strikingly, these agents trigger a catastrophic energy crisis by cooperatively suppressing glycolysis, the TCA cycle, and oxidative phosphorylation prior to cell death. EZH2 and PI3K pathway inhibitors achieve this by respectively inhibiting two key regulators of metabolism, MYC and HIF-1A, while concomitantly derepressing a pro-apoptotic stress sensor. Together, these studies reveal a promising therapeutic strategy for CRPC and demonstrate how metabolic plasticity can be fatally impaired by co-targeting upstream oncogenic nodes that converge on this important process.
The Journal of clinical investigation. 2026 Jun 09 [Epub ahead of print]
Rhea Sahu, Miriam Enos, Swastika Sharma, Amy E Schade, Alycia Gardner, Akiko Yoshinaga, Alexandra Indeglia, Eleanor Minogue, Songhua Hu, Kiran Kurmi, Shakchhi Joshi, Daniel R Schmidt, Samkyu Yaffe, Van Tm Nguyen, Fang Xie, Steven P Balk, Matthew G Vander Heiden, Kristian Helin, Marcia C Haigis, Karen Cichowski
Genetics Division, Department of Medicine, Brigham and Women's Hospital, Boston, United States of America., Department of Cell Biology, Harvard Medical School, Boston, United States of America., Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, United States of America., Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom., Division of Medical Oncology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States of America.