Key strategies to combat drug-resistant prostate cancer

Prostate cancer is the leading cause of cancer death among men, claiming more than 30,000 lives each year in the United States. Although most prostate cancers initially respond to androgen receptor blocking therapy, some tumors develop into a very aggressive, treatment-resistant form known as 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.

A new study conducted by Drs. Maria Diaz-Meco and Jorge Moscat, both the Homer T. Hurst III Professor of Oncology in Pathology and members of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, published Nov. 20 in the journal Natural communications, found that the absence of a protein called PKCλ/ι in prostate cancer cells allows EZH2 to promote aggressive growth even in the presence of androgen receptor inhibitors. Normally, PKCλ/ι limits the activity of EZH2. However, PKCλ/ι-deficient cells treated with androgen receptor inhibitors produce an alternative form of EZH2 that has a different function. Instead of repressing tumor suppressor genes, this form of EZH2 stimulates rapid protein production and activates growth factors such as TGF-β, creating an environment around the tumor that promotes cancer progression despite androgen receptor inhibition.

“This study reveals a critical mechanism of treatment resistance in prostate cancer, suggesting new therapeutic approaches,” said Dr. Diaz-Meco. “By understanding the role of EZH2 in this context, we may be able to re-sensitize tumors to androgen receptor inhibitors or make cancers re-vulnerable to targeted therapies such as immunotherapy.”

In preclinical studies, the team targeted alternative actions of EZH2 to evaluate potential treatment solutions. They found that inhibition of protein synthesis or the TGF-β pathway effectively reversed resistance in PKCλ/ι-deficient cancer cells. Blocking the alternative function of EZH2 restored sensitivity to androgen receptor therapies such as enzalutamide. Moreover, since TGF-β is associated with immune suppression in tumors, inhibition of this pathway may improve the effectiveness of immunotherapy, a treatment with limited success only in prostate cancer.

The researchers noted that the absence of PKCλ/ι creates a unique vulnerability in cancer cells, suggesting that combining EZH2 inhibitors with AR-targeting therapies could significantly inhibit tumor growth. However, they caution that EZH2 inhibition in tumors with high PKCl/i levels may sometimes counteract therapeutic effects, highlighting the need for precise treatment of patients with reduced PKCl/i levels. Given the complexity of the EZH2 pathway, achieving a careful balance is essential to avoid treatment reversal.

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

Dr. Moscat emphasized the collaborative efforts behind this study, building on previous findings on the role of PKCλ/ι in cancer progression. Co-authors of the study are postdoctoral fellow Dr. Shankha Chatterjee, faculty member Dr. Juan Linares, postdoctoral fellow Dr. Tania Cid-Diaz, and assistant professor of pathology and laboratory medicine research Dr. Angeles Duran, all members of the Moscata and Diaz-Meco Laboratories.