Cancer Cell | 乔源远团队揭示神经内分泌前列腺癌代谢“致命弱点”，提出全新联合治疗策略

TL;DR - A Cancer Cell paper from Yuanyuan Qiao and Arul Chinnaiyan (University of Michigan) identifies a "stress-adaptive lipid axis" that neuroendocrine prostate cancer (NEPC) depends on for survival, and shows that co-inhibiting the lipid kinase PIKfyve and fatty acid synthase (FASN) is synthetically lethal. It matters because NEPC is a highly aggressive, treatment-resistant subtype with ~7-month median survival and only limited platinum chemotherapy options.

• NEPC grows under severe hypoxia with chronic ER stress; it sustains a persistently active PERK–ATF4 UPR branch and overexpresses PIKfyve, making it selectively dependent on PIKfyve-driven endolysosomal trafficking and autophagic flux — knockout or inhibition kills NEPC cells while sparing conventional prostate cancer cells.
• PIKfyve inhibition triggers a compensatory escape route: SREBP activation drives de novo fatty acid/lipid synthesis to offset lysosomal dysfunction, defining the second arm of the proposed stress–lipid adaptation axis.
• Combining the PIKfyve inhibitor ESK981 with the FASN inhibitor TVB-2640 acted synergistically across cell lines, patient-derived organoids, and PDX models, converting the UPR from protective to pro-apoptotic and extending survival, with some models reaching complete response.
• Adding cisplatin further prolonged progression-free survival in animal models without notable added toxicity; both drug classes are already in clinical trials, supporting near-term translational testing.

Note: this summary is based on a Chinese-language WeChat write-up (BioArt) of the paper, not the primary article; it is biomedical/oncology research rather than an AI-methods advance.