Cancer Cell：乔源远团队发现神经内分泌前列腺癌的代谢弱点，提出联合治疗新策略

TL;DR - A Cancer Cell paper (Aug 3, 2026) from Yuanyuan Qiao's team at University of Michigan Ann Arbor identifies a "stress-adaptive lipid kinase axis" that lets neuroendocrine prostate cancer (NEPC) survive hypoxic, ER-stressed niches, and shows that co-inhibiting PIKfyve and FASN kills tumor cells. It matters because NEPC currently relies on short-lived, toxic platinum chemotherapy, so a synthetic-lethal metabolic target offers a new treatment route.

• NEPC (AR-signaling loss, gain of SYP/NSE markers, frequent RB1/TP53/PTEN loss, FOXA2/SOX2/ASCL1/ONECUT2 lineage programs) overexpresses the lipid kinase PIKfyve, which sustains lysosomal degradation and lipid recycling to maintain metabolic homeostasis under hypoxia.
• PIKfyve inhibition disrupts lysosomal function and worsens ER stress; tumors with high baseline ER stress are more sensitive to it.
• Cells compensate via an SREBP-dependent de novo lipogenesis program, creating a synthetic vulnerability between PIKfyve and fatty acid synthase (FASN).
• Dual PIKfyve + FASN inhibition synergistically amplifies ER stress, triggers a terminal unfolded protein response, induces apoptosis, and extends survival in preclinical models.