Dual inhibition of PIKfyve and FASN reveals therapeutic potential in neuroendocrine prostate cancer

Background : Neuroendocrine prostate cancer (NEPC) is emerging rapidly as a resistance phenotype to androgen receptor pathway inhibitors in castration-resistant prostate cancer. NEPC persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this hostile niche remain largely undefined. We hypothesized that NEPC depends on stress-adaptive lysosomal programs mediated by the lipid kinase PIKfyve that can be targeted therapeutically. Methods : PIKfyve expression was assessed by immunohistochemistry and RNA-ISH in clinical NEPC specimens. Functional studies used newly derived NEPC cell lines and established cell line (NCI-H660), and multiple NEPC PDX/CDX models. Pharmacologic and genetic perturbations of PIKfyve were evaluated in vitro and in vivo. Global transcriptomic, proteomic and lysosome-focused profiling were used to assess downstream responses. Combination studies explored the therapeutic impact of concurrently inhibiting PIKfyve and the lipogenic enzyme FASN. Cell death and pharmacodynamic endpoints included apoptotic markers and TUNEL staining. Results : PIKfyve was consistently elevated in primary and metastatic NEPC and was required for tumor cell survival. Pharmacologic inhibition of PIKfyve led to robust antitumor activity across multiple NEPC models, producing marked apoptosis and sustained tumor regressions. Multi-omic analyses indicated that PIKfyve inhibition activated compensatory lipid metabolic programs, including increased reliance on FASN. Notably, concurrent inhibition of PIKfyve and FASN resulted in enhanced tumor cell death and superior antitumor efficacy in vivo compared with single agents. Conclusions : NEPC exhibits a stress-associated metabolic dependency involving PIKfyve and adaptive lipogenic pathways. Co-targeting PIKfyve and FASN induces a potent therapeutic response in preclinical models, supporting further investigation of this combinatorial strategy as a promising approach for treating NEPC.