Discovery of the EZH2 enzyme in aggressive tumor growth of treatment-resistant prostate cancer

Treatment-resistant prostate cancer is a major challenge for physicians due to the lack of effective therapeutic options. However, a recent study conducted by scientists at Weill Cornell Medicine has revealed a surprising finding: the enzyme EZH2 plays a crucial role in the aggressive tumor growth of this cancer type. This discovery could open the door to new therapies that offer hope to patients facing limited treatment options.

The study, published in the journal Nature Communications, describes how the deficiency of PKCλ/ι in prostate cancer cells enables EZH2 activity, driving tumor growth despite the presence of androgen receptor inhibitors. This marks a significant advance in understanding treatment resistance mechanisms in prostate cancer, specifically in the subtype known as castration-resistant prostate cancer (CRPC).

The unexpected role of EZH2 in tumor progression

Traditionally, EZH2 has been associated with the repression of tumor suppressor genes, which limits the growth of cancerous cells. However, the researchers discovered that in the absence of PKCλ/ι, EZH2 adopts an alternative form that accelerates protein production and activates growth factors such as TGF-β, creating a favorable environment for cancer progression. This mechanism occurs even in cells treated with androgen receptor inhibitors like enzalutamide, which is typically used to slow prostate cancer growth.

The significance of this discovery lies in the fact that, by altering its function, EZH2 not only supports tumor survival but also contributes to the formation of a microenvironment that promotes tumor growth. This reveals a new pathway through which tumors can evade current treatments, highlighting the need for innovative therapeutic approaches to address resistance.

Potential therapies targeting EZH2 and TGF-β

The study suggests that by inhibiting EZH2’s alternative activities, it may be possible to restore tumor cell sensitivity to androgen receptor inhibitors. In preclinical studies conducted by the research team, blocking either protein synthesis or the TGF-β pathway led to a significant reversal of treatment resistance in PKCλ/ι-deficient prostate cancer cells. This intervention restored sensitivity to hormonal therapies such as enzalutamide, indicating that targeting this new pathway may overcome the resistance common in many CRPC cases.

Moreover, since TGF-β is linked to immune suppression within tumors, inhibiting this pathway could improve the effectiveness of treatments like immunotherapy—a therapeutic strategy that has shown limited success when used alone in prostate cancer. This combination therapy, targeting both EZH2 and TGF-β, may be a powerful way to enhance treatment options for patients with prostate cancer that is resistant to conventional therapies.

Implications for clinical practice: a personalized approach

The research also emphasizes the importance of a personalized approach in prostate cancer treatment. While EZH2 inhibition could benefit patients with PKCλ/ι deficiency, the researchers caution that in tumors with high levels of PKCλ/ι, inhibiting EZH2 might counteract therapeutic effects. This finding highlights the need for carefully tailored treatments that consider each patient’s specific molecular profile.

With these advances, scientists are opening a new line of research to develop combination treatments that precisely target the specific vulnerabilities of tumor cells. The next steps include planning clinical trials to test the combination of androgen receptor inhibitors with EZH2 or TGF-β inhibitors—an approach that could transform how treatment-resistant prostate cancer is managed.