Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

• 成果类型: Article
• 署名作者: Cheng, Caleb; Hu, Jing; Mannan, Rahul; He, Tongchen; Bhattacharyya, Rupam; Magnuson, Brian; Wisniewski, Jasmine P.; Peters, Sydney; Karim, Saadia A.; MacLean, David J.; Karaburk, Huseyin; Zhang, Li; Rossiter, Nicholas J.; Zheng, Yang; Xiao, Lanbo; Li, Chungen; Awad, Dominik; Mahapatra, Somnath; Bao, Yi; Zhang, Yuping; Cao, Xuhong; Wang, Zhen; Mehra, Rohit; Morlacchi, Pietro; Sahai, Vaibhav; di Magliano, Marina Pasca; Shah, Yatrik M.; Weisman, Lois S.; Morton, Jennifer P.; Ding, Ke; Qiao, Yuanyuan; Lyssiotis, Costas A.; Chinnaiyan, Arul M.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Shandong University; Central South University; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; Chinese Academy of Sciences; Shanghai Institute of Organic Chemistry, CAS; University of Michigan System; University of Michigan; Howard Hughes Medical Institute; Agilent Technologies; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Glasgow; University of Michigan System; University of Michigan
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2351
• DOI: 10.1038/s41586-025-08917-z
• 发表日期: 2025-06-19
• 关键词: kinase inhibitor; identification; autophagy; protein; tumors

摘要

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes3, 4-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the difficulty in identifying and characterizing favourable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase that is integral to lysosomal functioning7, as a targetable vulnerability in PDAC. Using a genetically engineered mouse model, we established that PIKfyve is essential to PDAC progression. Furthermore, through comprehensive metabolic analyses, we found that PIKfyve inhibition forces PDAC to upregulate a distinct transcriptional and metabolic program favouring de novo lipid synthesis. In PDAC, the KRAS-MAPK signalling pathway is a primary driver of de novo lipid synthesis. Accordingly, simultaneously targeting PIKfyve and KRAS-MAPK resulted in the elimination of the tumour burden in numerous preclinical human and mouse models. Taken together, these studies indicate that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.