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
  • 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.
Products