UC Davis

Neuroendocrine prostate cancer (NEPC) represents an aggressive subtype of prostate cancer, which may either manifest de novo or emerge because of anti-androgen receptor (AR) drug treatment. Unfortunately, there is currently no established effective treatment for NEPC. Alectinib and entrectinib are FDA-approved receptor tyrosine kinase inhibitors designed to target the anaplastic lymphoma kinase receptor (ALK) initially developed for NSCLC patients who developed resistance to the receptor tyrosine kinase (RTK) inhibitor crizotinib. In this study, we sought to assess the potential of alectinib and entrectinib as therapeutic agents for NEPC. We conducted experiments using various NEPC cell lines and castration-resistant prostate cancer (CRPC) cells, subjecting them to treatment with alectinib and entrectinib. Notably, treatment with these drugs, particularly in cell lines 42D, NCI-H660, C42B-entry, and LuCaP, significantly inhibited cell growth and proliferation. Further investigation revealed that alectinib and entrectinib exerted their effects by impacting the ALK signaling pathway. Specifically, downstream targets of ALK signaling, such as STAT3 and AKT phosphorylation, exhibited reductions in treated cells. Additionally, the expression of NEPC cellular markers, including enolase2, BRN2, and ASCL1, decreased upon alectinib treatment. Notably, NEPC tumors treated with alectinib or entrectinib in combination with CM 272, a G9a/DMNT1 inhibitor, exhibited a notable decrease in tumor volume. Both alectinib and entrectinib demonstrated their efficacy in inhibiting various cellular pathways, including the Neuroactive ligand-receptor and cytokine-to-cytokine receptor interaction pathways. The findings of our current study provide compelling evidence that alectinib and entrectinib have the potential to effectively inhibit NEPC cell and tumor growth. Consequently, these drugs hold promise as therapeutics for patients grappling with NEPC, offering a potential avenue for improved treatment outcomes.