Rb and p53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance

Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting lineage plasticity facilitates therapeutic resistance. Mechanisms underlying prostate cancer lineage plasticity are unknown, and relevant experimental models are needed. We demonstrate Rb1 loss facilitates lineage plasticity and metastasis of prostate adenocarcinoma initiated by Pten mutation in the mouse. Additional loss of Trp53 causes resistance to antiandrogen therapy. Gene expression profiling indicates mouse tumors are comparable to human prostate cancer neuroendocrine variants; both mouse and human tumors exhibit increased expression of epigenetic reprogramming factors like Ezh2 and Sox2. Clinically relevant Ezh2 inhibitors restore androgen receptor expression and sensitivity to antiandrogen therapy. These findings uncover genetic mutations enabling prostate cancer progression, identify mouse models for studying prostate cancer lineage plasticity, and suggest an epigenetic approach for extending clinical responses to antiandrogen therapy.