NCOA4-mediated ferritinophagy is a pancreatic cancer dependency via maintenance of iron bioavailability for iron-sulfur cluster proteins

Oncogenic KRAS rewires pancreatic ductal adenocarcinoma (PDAC) metabolism to promote dependence on autophagy and iron metabolism. NCOA4-mediated ferritinophagy links autophagy and iron metabolism as NCOA4 selectively targets ferritin, the cellular iron storage complex, via autophagy to the lysosome for ferritin degradation and release of iron for utilization. Using patient-derived and genetically engineered murine models of PDAC we now demonstrate that ferritinophagy is upregulated in PDAC to sustain iron availability thereby promoting PDAC progression. PDAC global quantitative proteomics reveals that ferritinophagy fuels iron-sulfur cluster synthesis to support mitochondrial homeostasis. Targeting NCOA4 leads to tumor growth delay and prolonged survival but with development of compensatory iron acquisition pathways. Finally, a ferritinophagy gain-of-function PDAC murine model demonstrates worse survival, and an elevated ferritinophagy expression signature predicts for worse overall survival in human PDAC patients. Together, our data define NCOA4-mediated ferritinophagy as a therapeutic target in PDAC and reveal that maintenance of cellular iron homeostasis is a critical cell autonomous function of PDAC autophagy.