Targeting PIKfyve-driven lipid metabolism in pancreatic cancer

Date:	June 2025
PMID:	https://pmc.ncbi.nlm.nih.gov/articles/PMC12176661/
Category:	N/A
Authors:	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, Arul M Chinnaiyan
Abstract:

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism^1,2. For example, PDAC uses, and is dependent on, high levels of autophagy and other lysosomal processes^3-5. 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.

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center