The kinase PLK1 promotes Hedgehog signaling–dependent resistance to the antiandrogen enzalutamide in metastatic prostate cancer

Enzalutamide, a second-generation androgen receptor inhibitor (also known as an antiandrogen), is used to treat patients with metastatic castration-resistant prostate cancer (CRPC). Tumors often acquire resistance to enzalutamide. Tumor progression and enzalutamide resistance are associated with decreased abundance of the tumor suppressor PDCD4. In normal dividing cells, PDCD4 abundance is low when that of the kinase PLK1 is high. In this study, we found that PLK1 acted on PDCD4 to promote enzalutamide resistance in CRPC cells in culture and in mice via a mechanism that revealed an effective combination therapy. PLK1 phosphorylated PDCD4 at Ser²³⁹, leading to its degradation and consequently inducing the transcriptional activation of Hedgehog (Hh) signaling by c-MYC. Hh signaling supports tumor cell proliferation and stemness by inducing the enzyme UDP-glucuronosyltransferase 2B15 (UGT2B15), which promotes the metabolic clearance of drugs and steroid hormones. Thus, this pathway may circumvent androgen receptor dependence, thereby reducing cellular sensitivity to enzalutamide. Knocking down UGT2B15 enhanced enzalutamide-induced cell apoptosis and growth arrest in a PDCD4-dependent manner. Combining enzalutamide with the clinically approved Hh pathway inhibitor vismodegib inhibited cell growth and promoted apoptosis in enzalutamide-resistant cell cultures and xenografts in vivo. Our findings reveal a mechanism of PLK1-mediated enzalutamide resistance and suggest a potential therapeutic strategy to overcome this resistance in prostate cancer.