Targeting the ferritinophagy-lysosome axis as a therapeutic vulnerability in gastroenteropancreatic neuroendocrine tumors - PubMed
5 hours ago
- #PIKfyve
- #ferritinophagy
- #GEP-NETs
- mTOR inhibitors (mTORis) are FDA-approved for advanced GEP-NETs but face limited efficacy due to transient responses and resistance.
- A kinome-wide CRISPR-Cas9 screen identifies PIKfyve as a key vulnerability in GEP-NETs, linked to lipid biosynthesis via the mTOR-SREBP1 axis.
- PIKfyve inhibition disrupts lysosome-mediated ferritin degradation, exacerbating metabolic stress from mTORi-induced ferritinophagy.
- Combined inhibition of mTOR and PIKfyve synergistically disrupts lipid and iron metabolism, enhancing tumor suppression and survival in preclinical models.
- PIKfyve is proposed as a metabolic co-target to overcome mTORi resistance, suggesting new combination therapies for mTOR-driven cancers.