PIKfyve-regulated lipid metabolism as a therapeutic vulnerability in neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) is a lethal, androgen receptor (AR)-independent subtype of prostate cancer that often arises after AR pathway inhibition and has limited treatment options. We hypothesized that NEPC might be susceptible to metabolic interventions targeting PIKfyve. Here, we identify the lipid kinase PIKfyve as overexpressed in advanced prostate cancers and find that NEPC cells are especially dependent on PIKfyve-driven lipid metabolism. Pharmacological PIKfyve inhibition triggered rapid apoptosis in NEPC cells. Mechanistically, AR pathway loss in NEPC reprogrammed tumor cells to tolerate sustained stress through autophagy. PIKfyve blockade forced NEPC cells to rely on de novo lipid synthesis for survival, and accordingly, dual inhibition of PIKfyve and de novo lipid synthesis synergistically suppressed NEPC tumor growth. These findings reveal a unique metabolic vulnerability in NEPC and suggest that targeting PIKfyve-dependent lipid metabolism could be a promising therapeutic strategy for this aggressive prostate cancer subtype.