A groundbreaking study from Weill Cornell Medicine offers new hope for patients battling castration-resistant prostate cancer (CRPC), a particularly aggressive form of the disease. Published in Nature Communications, the research pinpoints the enzyme EZH2 as a key driver of tumor growth in CRPC that has become resistant to standard treatments. This discovery opens exciting avenues for the development of novel therapies that could re-sensitize tumors to existing drugs or make them vulnerable to other treatments like immunotherapy.

At the heart of this finding lies a complex interplay between EZH2 and a protein kinase called PKCλ/ι. In normal prostate cells, PKCλ/ι acts as a regulator, keeping EZH2’s activity in check. However, the research team observed that when PKCλ/ι is absent in prostate cancer cells, EZH2 is free to fuel aggressive tumor growth, even in the presence of androgen receptor inhibitors, a common treatment for CRPC.

The absence of PKCλ/ι not only unleashes EZH2 but also leads to the production of an alternative form of the enzyme with a dramatically different function. Instead of suppressing tumor-suppressing genes, this altered EZH2 ramps up protein production and activates growth factors like TGF-β, creating an environment conducive to cancer progression despite androgen receptor inhibition.

The study’s preclinical findings suggest several promising therapeutic strategies. Inhibiting either 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 like enzalutamide. Moreover, targeting the TGF-β pathway, known to suppress immune responses in tumors, could potentially enhance the effectiveness of immunotherapy, a treatment that has shown limited success against prostate cancer alone.

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