Key strategies against drug-resistant prostate cancer

Prostate cancer is a leading cause of cancer-related death in men, claiming over 30,000 lives annually in the United States. While most prostate cancers initially respond to androgen receptor-blocking therapies, some tumors progress to an extremely aggressive, treatment-resistant form called neuroendocrine prostate cancer, which no longer relies on androgen signaling and is therefore difficult to treat. Understanding this transition has become a priority for researchers and clinicians.

The new study led by Dr. Maria Diaz-Meco and Jorge Moscat, both Homer T. Hirst III Professors of Oncology in Pathology and members of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and published November 20 in nature communication, found that the absence of a protein called PKCλ/ι in prostate cancer cells allows EZH2 to drive aggressive growth even in the presence of androgen receptor inhibitors. Normally, PKCλ/ι limits the activity of EZH2. However, in PKCλ/ι-deficient cells treated with androgen receptor inhibitors, an alternative form of EZH2 is produced that has a different function. Instead of suppressing tumor suppressor genes, this form of EZH2 drives rapid protein production and activates growth factors such as TGF-β, creating an environment around the tumor that promotes cancer progression despite inhibiting the androgen receptor.

“This study uncovers a critical mechanism behind treatment resistance in prostate cancer and suggests new therapeutic approaches,” said Dr. Diaz Meco. “If we understand the role of EZH2 in this context, we may be able to re-sensitize tumors to androgen receptor inhibitors or make the cancer newly susceptible to targeted treatments such as immunotherapies.”

In preclinical studies, the team focused on EZH2’s alternative activities to evaluate possible treatment solutions. They found that inhibiting either protein synthesis or TGF-β signaling effectively reversed resistance in PKCλ/ι-deficient cancer cells. Blocking the alternative function of EZH2 restored sensitivity to androgen receptor therapies such as enzalutamide. Furthermore, because TGF-β is associated with immunosuppression in tumors, inhibiting this pathway could improve the effectiveness of immunotherapy, a treatment with limited success against prostate cancer alone.

The researchers found that the absence of PKCλ/ι creates a unique vulnerability for cancer cells, suggesting that combining EZH2 inhibitors with AR-targeted therapies could significantly inhibit tumor growth. However, they warn that inhibition of EZH2 in tumors with high PKCl/i levels can sometimes counteract therapeutic effects, highlighting the need for precisely tailored treatments for patients with reduced PKCl/i levels. Given the complexity of the EZH2 signaling pathway, it is important to achieve a careful balance to avoid negating treatment benefits.

This research lays the foundation for clinical trials combining androgen receptor inhibitors with EZH2 or TGF-β inhibitors for patients with refractory prostate cancer characterized by PKCλ/ι deficiency. Targeting these signaling pathways offers hope not only to overcome AR resistance but also to expand treatment options for this challenging form of cancer.

Dr. Moscat highlighted the collaborative effort behind this study, which builds on previous findings on the role of PKCλ/ι in cancer progression. The co-first authors of the study are postdoctoral researcher Dr. Shankha Chatterjee, the lecturer Dr. Juan Linares, the postdoctoral researcher Dr. Tania Cid-Diaz and assistant professor of pathology and laboratory medicine Dr. Angeles Duran, all members of the Moscat and Diaz-Meco laboratories.