A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer
Zheng, Y.; Cheng, C.; Cao, Y.; Cruz, G.; Zhang, Y.; Paturu, R.; Mahapatra, S.; Hu, J.; Mannan, R.; Karabürk, H.; Bhattacharyya, R.; Yin, Y.; Zhao, Y.; Liu, W.; Cao, X.; Xue, H.; Li, C.; Wang, Z.; Miner, S. J.; Vaishampayan, U.; Sahai, V.; Weisman, L. S.; Ding, K.; Lyssiotis, C. A.; Wang, Y.; Qiao, Y.; Chinnaiyan, A. M.
Show abstract
Neuroendocrine prostate cancer (NEPC) persists in a profoundly hypoxic microenvironment, yet the mechanisms enabling tumor adaptation to this metabolically challenging niche remain undefined. Here, we identify the lipid kinase PIKfyve as overexpressed in NEPC, functioning as a central node in a stress-lipid kinase axis that drives adaptation to persistent endoplasmic reticulum (ER) stress. Mechanistically, NEPC requires PIKfyve-mediated lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia. PIKfyve inhibition disrupts lysosomal function, leading to ER stress accumulation and activation of a compensatory, sterol regulatory element-binding protein (SREBP)-dependent de novo lipogenesis program essential for NEPC survival. This stress-lipid axis creates a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN), where dual inhibition synergistically amplifies ER stress, triggers the terminal unfolded protein response, and induces tumor cell death. These findings reveal a metabolic adaptation in NEPC and provide preclinical evidence that co-targeting PIKfyve and FASN can overcome hypoxia-associated stress adaptation.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.