Disrupted clock pathway during lineage plasticity and prostate cancer progression

Most treatment resistant prostate cancers are driven by androgen receptor (AR) signaling. However, AR-negative prostate cancer has been increasingly recognized as the mechanism of resistance, particularly as potent AR-targeted therapies have been introduced earlier in the treatment paradigm. Lineage plasticity and histologic transformation of AR-driven prostate adenocarcinoma to AR-negative neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer. Here, we explored how the circadian clock pathway changes occur during lineage plasticity and prostate cancer progression. We identified loss of rhythmicity in the expression of clock regulated genes. Clock pathway regulators RORalpha, BMAL1, and CLOCK are highly expressed in NEPC compared to prostate adenocarcinoma. RORA displays marked upregulation in prostate tumors after AR targeted therapy relative to matched pre-therapy tumors. RORA overexpression in prostate adenocarcinoma models led to increased cell proliferation and enriched cell cycle pathway. Importantly, we noted that clock pathway is reprogrammed differently in AR-dependent and AR-independent prostate tumors. For instance, RORA overexpression in AR-dependent adenocarcinoma cells resulted in enriched androgen response and enhanced sensitivity towards AR-targeted pathway inhibitors. RORA knockout in AR-independent models resulted in increased expression of mitochondrial genes and increased sensitivity towards oxidative phosphorylation (OXPHOS) inhibitors. Moreover, targeting RORalpha in NEPC patient-derived organoids and mouse xenograft models abrogated tumor growth and downregulated the NEPC phenotype. Altogether, our findings point to a mechanistic regulation of clock genes including RORalpha during prostate cancer progression and nominates potential new strategies to target lineage plasticity.