A stress-adaptive lipid kinase axis defines metabolic vulnerabilities in neuroendocrine prostate cancer.
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-adaptive lipid kinase axis that supports 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, exacerbates ER stress, and activates 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.
EDRN PI Authors
Medline Author List
- Bhattacharyya R
- Cao X
- Cao Y
- Cheng C
- Chinnaiyan AM
- Cruz G
- Ding K
- Hu J
- Karabürk H
- Li C
- Liu W
- Lyssiotis CA
- Mahapatra S
- Mannan R
- Mehra R
- Miner SJ
- Paturu R
- Qiao Y
- Reichert ZR
- Sahai V
- Vaishampayan U
- Wang Y
- Wang Z
- Weisman LS
- Xue H
- Yin Y
- Zhang Y
- Zhao Y
- Zheng Y