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

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.