Researchers at Weill Cornell Medicine have identified a novel role for the enzyme EZH2 in promoting aggressive tumor growth in treatment-resistant prostate cancers. The study, published in Nature Communications, reveals that EZH2, regulated by the protein kinase PKCλ/ι, contributes to tumor progression by evading proteasomal degradation, offering a potential therapeutic target for patients with limited options.
EZH2's Role in Castration-Resistant Prostate Cancer
The study, led by Maria Diaz-Meco, PhD, and Jorge Moscat, PhD, investigated the mechanisms of resistance in castration-resistant prostate cancer (CRPC). The researchers found that the absence of the protein PKCλ/ι in prostate cancer cells enables EZH2 to drive aggressive growth, even when androgen receptor inhibitors are present. This is because, normally, PKCλ/ι limits EZH2’s activity.
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 around the tumor 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," explained Diaz-Meco. The researchers observed that inhibiting either protein synthesis or the TGF-β pathway effectively reversed resistance in PKCλ/ι-deficient cancer cells in preclinical studies. Blocking EZH2’s alternative function restored sensitivity to androgen receptor therapies like enzalutamide.
Furthermore, given that TGF-β is associated with immune suppression in tumors, inhibiting this pathway could enhance immunotherapy effectiveness, a treatment with limited success against prostate cancer alone. The scientists noted that the absence of PKCλ/ι creates a unique vulnerability in cancer cells, suggesting that combining EZH2 inhibitors with AR-targeted therapies could significantly inhibit tumor growth.
Cautions and Future Directions
However, the researchers caution that inhibiting EZH2 in tumors with high levels of PKCλ/ι can sometimes counteract therapeutic effects, underscoring the need for precisely tailored treatments for patients with reduced PKCλ/ι levels. Achieving a careful balance is essential to avoid reversing treatment benefits, given the complexity of the EZH2 pathway.
The new study lays the groundwork for clinical trials combining androgen receptor inhibitors with EZH2 or TGF-β inhibitors for patients with therapy-resistant prostate cancer characterized by PKCλ/ι deficiency.
