Scientists at Weill Cornell Medicine have identified a critical mechanism that drives treatment-resistant prostate cancer, potentially opening new avenues for therapies for patients with limited options. The study, published in Nature Communications, elucidates the role of the enzyme EZH2 in promoting tumor growth in aggressive prostate cancer.
Prostate cancer remains a significant cause of cancer-related deaths among men, with over 30,000 deaths annually in the U.S. While initial therapies targeting androgen receptors are often effective, some tumors evolve into neuroendocrine prostate cancer, a highly aggressive form that is resistant to these treatments. This resistance prompts investigations into underlying mechanisms.
The study reveals that in the absence of the protein PKCλ/ι, EZH2 alters its function. Instead of suppressing tumor growth by repressing specific genes, EZH2 activates protein synthesis and growth factors such as TGF-β. This creates an environment that promotes tumor progression despite the use of androgen receptor inhibitors like enzalutamide.
Novel Therapeutic Approaches
"This study reveals a critical mechanism behind treatment resistance in prostate cancer, suggesting new therapeutic approaches," said Dr. Maria Diaz-Meco, the Homer T. Hirst III Professor of Oncology in Pathology.
Preclinical experiments have demonstrated that targeting EZH2’s alternative activities can reverse drug resistance. Inhibiting protein synthesis or the TGF-β pathway re-sensitized cancer cells lacking PKCλ/ι to androgen receptor inhibitors. Given TGF-β's association with immune suppression in tumors, blocking this pathway could also enhance the effectiveness of immunotherapies, which have had limited success in prostate cancer.
The absence of PKCλ/ι in cancer cells presents a unique vulnerability. Combining androgen receptor inhibitors with EZH2 or TGF-β inhibitors could suppress tumor growth. However, researchers emphasize that the therapeutic impact of targeting EZH2 depends on the tumor’s specific molecular profile, highlighting the need for precision medicine approaches.
Future Clinical Trials
"This work builds on our previous findings and highlights the collaborative efforts of our research team," said Dr. Jorge Moscat, also a Homer T. Hirst III Professor of Oncology in Pathology.
The discovery may pave the way for clinical trials that combine androgen receptor inhibitors with targeted therapies against EZH2 or TGF-β, offering new hope for patients with advanced, drug-resistant prostate cancer. The research was supported by grants from the National Cancer Institute and the National Institute of General Medical Sciences.
