A new study from Weill Cornell Medicine reveals that the enzyme EZH2 plays a critical role in promoting aggressive tumor growth in treatment-resistant prostate cancers. The research, published in Nature Communications, identifies potential new therapeutic strategies for patients with limited treatment options, particularly those whose cancers have developed resistance to androgen receptor-blocking therapies.
The Role of EZH2 in Treatment Resistance
Prostate cancer remains a leading cause of cancer-related deaths in men. While initial treatments targeting androgen receptors are often effective, some tumors evolve into a highly aggressive, treatment-resistant form known as neuroendocrine prostate cancer. Drs. Maria Diaz-Meco and Jorge Moscat led the study, which uncovered that the absence of the protein PKCλ/ι in prostate cancer cells allows EZH2 to drive aggressive growth, even when androgen receptor inhibitors are present.
Normally, PKCλ/ι limits EZH2’s activity. However, in PKCλ/ι-deficient cells treated with androgen receptor inhibitors, an alternative form of EZH2 is produced with a different function. Instead of repressing tumor-suppressor genes, this form of EZH2 drives rapid protein production and activates growth factors like TGF-β, fostering an environment that promotes cancer progression despite androgen receptor inhibition.
Potential Therapeutic Approaches
"This study reveals a critical mechanism behind treatment resistance in prostate cancer, suggesting new therapeutic approaches," said Dr. Diaz-Meco. The team's preclinical studies showed that inhibiting either protein synthesis or the TGF-β pathway effectively reversed resistance in PKCλ/ι-deficient cancer cells. Blocking EZH2’s alternative function restored sensitivity to androgen receptor therapies like enzalutamide. Furthermore, inhibiting TGF-β, which is associated with immune suppression in tumors, could enhance immunotherapy effectiveness.
The researchers caution that inhibiting EZH2 in tumors with high levels of PKCl/i can sometimes counteract therapeutic effects, underscoring the need for precisely tailored treatments for patients with reduced PKCl/i levels. Achieving a careful balance is essential to avoid reversing treatment benefits, given the complexity of the EZH2 pathway.
Implications for Clinical Trials
This research supports the initiation of clinical trials combining androgen receptor inhibitors with EZH2 or TGF-β inhibitors for patients with therapy-resistant prostate cancer characterized by PKCλ/ι deficiency. Targeting these pathways offers hope not only to overcome AR resistance but also to broaden treatment options for this challenging form of cancer. Dr. Moscat emphasized the collaborative efforts behind this study, building on previous findings about PKCλ/ι’s role in cancer progression.
