PT  - JOURNAL ARTICLE
AU  - Maria Chiara De Santis
AU  - Luca Gozzelino
AU  - Jean Piero Margaria
AU  - Andrea Costamagna
AU  - Edoardo Ratto
AU  - Federico Gulluni
AU  - Enza Di Gregorio
AU  - Erica Mina
AU  - Nicla Lorito
AU  - Marina Bacci
AU  - Rossano Lattanzio
AU  - Gianluca Sala
AU  - Paola Cappello
AU  - Francesco Novelli
AU  - Elisa Giovannetti
AU  - Caterina Vicentini
AU  - Silvia Andreani
AU  - Pietro Delfino
AU  - Vincenzo Corbo
AU  - Aldo Scarpa
AU  - Paolo Ettore Porporato
AU  - Andrea Morandi
AU  - Emilio Hirsch
AU  - Miriam Martini
TI  - Lysosomal lipid switch sensitises to nutrient deprivation and mTOR targeting in pancreatic cancer
AID  - 10.1136/gutjnl-2021-325117
DP  - 2023 Feb 01
TA  - Gut
PG  - 360--371
VI  - 72
IP  - 2
4099  - http://gut.bmj.com/content/72/2/360.short
4100  - http://gut.bmj.com/content/72/2/360.full
SO  - Gut2023 Feb 01; 72
AB  - 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-C2γ protein abundance with disease outcome. Mechanisms were then studied in mouse (KPC mice) and cellular models of PDAC, in presence or absence of PI3K-C2γ (WT or KO). PI3K-C2γ-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-C2γ expression was reduced in about 30% of PDAC cases and was associated with an aggressive phenotype. Similarly, loss of PI3K-C2γ in KPC mice enhanced tumour development and progression. The increased aggressiveness of tumours lacking PI3K-C2γ correlated with hyperactivation of mTORC1 pathway and glutamine metabolism rewiring to support lipid synthesis. PI3K-C2γ-KO tumours failed to adapt to metabolic stress induced by glutamine depletion, resulting in cell death.Conclusion Loss of PI3K-C2γ 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-C2γ loss.Data are available in a public, open access repository. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.