Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer

Objective Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited therapeutic options. However, metabolic adaptation to the harsh PDAC environment can expose liabilities useful for therapy. Targeting the key metabolic regulator mechanistic target of rapamycin complex 1 (mTORC1) and its downstream pathway shows efficacy only in subsets of patients but gene modifiers maximising response remain to be identified. Design Three independent cohorts of PDAC patients were studied to correlate PI3K-C2 gamma protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2 gamma (WT or KO). PI3K-C2 gamma-dependent metabolic rewiring and its impact on mTORC1 regulation were assessed in conditions of limiting glutamine availability. Finally, effects of a combination therapy targeting mTORC1 and glutamine metabolism were studied in WT and KO PDAC cells and preclinical models. Results PI3K-C2 gamma expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2 gamma in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2 gamma correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2 gamma-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death. Conclusion Loss of PI3K-C2 gamma prevents mTOR inactivation and triggers tumour vulnerability to RAD001 (mTOR inhibitor) and BPTES/CB-839 (glutaminase inhibitors). Therefore, these results might open the way to personalised treatments in PDAC with PI3K-C2 gamma loss.