Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

Caleb Cheng, Jing Hu, Rahul Mannan, Tongchen He, Rupam Bhattacharyya, Brian Magnuson, Jasmine P. Wisniewski, Sydney Peters, Saadia A. Karim, David J. MacLean, Hüseyin Karabürk, Li Zhang, Nicholas J. Rossiter, Yang Zheng, Lanbo Xiao, Chungen Li, Dominik Awad, Somnath Mahapatra, Yi Bao, Yuping Zhang, Xuhong Cao, Zhen Wang, Rohit Mehra, Pietro Morlacchi, Vaibhav Sahai, Marina Pasca di Magliano, Yatrik M. Shah, Lois S. Weisman, Jennifer P. Morton, Ke Ding, Yuanyuan Qiao (), Costas A. Lyssiotis () and Arul M. Chinnaiyan ()
Additional contact information
Caleb Cheng: University of Michigan
Jing Hu: University of Michigan
Rahul Mannan: University of Michigan
Tongchen He: University of Michigan
Rupam Bhattacharyya: University of Michigan
Brian Magnuson: University of Michigan
Jasmine P. Wisniewski: University of Michigan
Sydney Peters: University of Michigan
Saadia A. Karim: CRUK Scotland Institute
David J. MacLean: CRUK Scotland Institute
Hüseyin Karabürk: University of Michigan
Li Zhang: University of Michigan
Nicholas J. Rossiter: University of Michigan
Yang Zheng: University of Michigan
Lanbo Xiao: University of Michigan
Chungen Li: Chinese Academy of Sciences
Dominik Awad: University of Michigan
Somnath Mahapatra: University of Michigan
Yi Bao: University of Michigan
Yuping Zhang: University of Michigan
Xuhong Cao: University of Michigan
Zhen Wang: Chinese Academy of Sciences
Rohit Mehra: University of Michigan
Pietro Morlacchi: Agilent Technologies
Vaibhav Sahai: University of Michigan
Marina Pasca di Magliano: University of Michigan
Yatrik M. Shah: University of Michigan
Lois S. Weisman: University of Michigan
Jennifer P. Morton: CRUK Scotland Institute
Ke Ding: Chinese Academy of Sciences
Yuanyuan Qiao: University of Michigan
Costas A. Lyssiotis: University of Michigan
Arul M. Chinnaiyan: University of Michigan

Nature, 2025, vol. 642, issue 8068, 776-784

Abstract: Abstract 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 processes3–5. 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.

Date: 2025
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DOI: 10.1038/s41586-025-08917-z

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