2. Academic Validation
  3. Targeting the ferritinophagy-lysosome axis as a therapeutic vulnerability in gastroenteropancreatic neuroendocrine tumors

Targeting the ferritinophagy-lysosome axis as a therapeutic vulnerability in gastroenteropancreatic neuroendocrine tumors

  • Cell Rep Med. 2026 Apr 21;7(4):102695. doi: 10.1016/j.xcrm.2026.102695.
Yizhi Cao 1,  Caleb Cheng 2,  Yitong Yin 3,  Sarah N Yee 3,  Yang Zheng 3,  Somnath Mahapatra 3,  Radha Paturu 3,  Andrej Coleski 3,  Shannon VanAken 3,  Fan Yang 3,  Rüya Pakkan 3,  Yi Zhao 1,  Rupam Bhattacharyya 3,  Stephanie J Miner 3,  Xuhong Cao 3,  Rahul Mannan 3,  Chungen Li 4,  Vaibhav Sahai 5,  Ke Ding 4,  Costas A Lyssiotis 6,  Arul M Chinnaiyan 7,  Yuanyuan Qiao 8
Affiliations

Affiliations

  • 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
  • 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • 3 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 4 State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, P.R. China.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 6 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
  • 7 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
  • 8 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
PMID: 41881024 DOI: 10.1016/j.xcrm.2026.102695
Abstract

mTOR inhibitors (mTORis) are Food and Drug Administration (FDA)-approved therapies for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), yet their clinical efficacy is often limited by transient responses and acquired resistance. To uncover sensitizing co-targets, we conduct a kinome-wide CRISPR-Cas9 screen, identifying the lipid kinase PIKfyve as a key vulnerability in GEP-NETs. PIKfyve is overexpressed and functionally linked to the regulation of lipid biosynthesis through the mTOR-SREBP1 axis. Mechanistically, PIKfyve inhibition impairs lysosome-mediated ferritin degradation, amplifying metabolic stress triggered by mTORi-induced ferritinophagy. Co-inhibition of mTOR and PIKfyve synergistically disrupts lipid and iron metabolism, leading to enhanced tumor suppression and improved survival in preclinical GEP-NET models. These findings nominate PIKfyve as a metabolic co-target to overcome mTORi resistance, offering a rationale for combination therapies in mTOR-driven malignancies.

Keywords

PIKfyve; ferritinophagy; gastroenteropancreatic neuroendocrine tumor; lipid metabolism; lysosome; mTOR.

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