Inositol Polyphosphate-4-Phosphatase Type II promotes gemcitabine resistance in pancreatic ductal adenocarcinoma cells via lysosomal exocytosis
Chemotherapy resistance is a major challenge in pancreatic ductal adenocarcinoma (PDAC). While high Inositol Polyphosphate-4-Phosphatase Type II (INPP4B) expression correlates with poor outcomes, its function in chemotherapy response is unclear. We show that INPP4B promotes gemcitabine resistance by enhancing lysosomal exocytosis. Across PDAC models, high INPP4B linked to reduced gemcitabine…
Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge due to chemotherapy resistance. Recent studies have revealed a potential link between Inositol Polyphosphate-4-Phosphatase Type II (INPP4B) expression and poor treatment outcomes. INPP4B appears to enhance gemcitabine resistance by promoting lysosomal exocytosis.
In PDAC models, higher INPP4B levels were associated with reduced sensitivity to gemcitabine, while its inhibition restored the drug's effectiveness. Furthermore, INPP4B conferred resistance to a variety of chemotherapy agents, including irinotecan, oxaliplatin, paclitaxel, and daunorubicin. Mechanistically, INPP4B elevated the expression of cell-surface LAMP1, facilitating extracellular gemcitabine release, and counteracting DNA damage.
Pharmacological intervention with lysosomal inhibitors like chloroquine, Bafilomycin A, or specific PIKfyve or TRPML1 inhibitors blocked exocytosis and re-established gemcitabine sensitivity in vitro. Additionally, chloroquine co-treatment restored gemcitabine efficacy in PDAC xenografts. These findings establish INPP4B-driven lysosomal exocytosis as a critical mechanism underlying gemcitabine resistance, suggesting a promising therapeutic target for enhancing PDAC resensitization.
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