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AACR 2023: Researchers Focus on Solving the Enzalutamide Efficacy Puzzle in Prostate Cancer

By: Celeste L. Dixon
Posted: Friday, April 28, 2023

Inhibition or loss of Porcupine (a Wnt-specific acyltransferase) may result in regaining enzalutamide sensitivity in enzalutamide-resistant, castration-resistant prostate cancer models, according to work presented by Katelyn Makayla Jones, BS, and Xiaoqi Liu, PhD, of the University of Kentucky, Lexington, at the American Association for Cancer Research (AACR) Annual Meeting 2023 (Abstract 1077/21). The pair set out to explore the mechanisms of the Porcupine and Wnt signaling cascades in the hopes of learning why the androgen receptor–signaling inhibitor enzalutamide provides improvement in castration-resistant prostate cancer for only about 2 months before the disease progresses. Their preclinical work uncovered not only that Porcupine and Wnt signaling cascades are paramount to contributing to androgen receptor activation, but this promotes both the cancer’s progression to incurability and the development of enzalutamide resistance.

Further, they demonstrated that using a combination of β-catenin inhibitor with enzalutamide resulted in the synergistic inhibition of patient-derived xenograft tumor growth. Additionally, they found that when the downstream effector ROCK is depleted, or when depleted ROCK cells are treated with enzalutamide, cell migration and invasion are hindered significantly. Thus, “utilizing a combination therapy of a ROCK inhibitor with enzalutamide synergistically inhibited the growth of [xenograft] tumors,” they noted.

“Simultaneously inhibiting both the canonical and noncanonical Wnt signaling cascade will result in the inhibition of cell proliferation, migration, and invasion,” wrote the researchers. An inhibition or loss of Porcupine “resulted in the regain of enzalutamide sensitivity in enzalutamide-resistant models.” Drs. Jones and Liu said they confirmed the contributions of both the canonical and noncanonical Wnt pathways to the tumor-cell invasion and migration that lead to metastasis in enzalutamide-resistant castration-resistant prostate cancer.

Disclosure: The study authors reported no conflicts of interest.

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