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.

doi:10.64898/2026.06.15.732391

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bioRxiv · 10.64898/2026.06.15.732391

A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer

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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.

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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.. 2026-06-18. A Stress-Adaptive Lipid Kinase Axis Defines Metabolic Vulnerabilities in Neuroendocrine Prostate Cancer. https://doi.org/10.64898/2026.06.15.732391

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