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Abstract
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.
- SIGNAL TRANSDUCTION
- PANCREATIC CANCER
- LIPID METABOLISM
- CELL BIOLOGY
- AMINO ACIDS
Data availability statement
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.
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Data availability statement
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.
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Twitter @SilviaAndreani7
EH and MM contributed equally.
Contributors Conceptualisation: MCDS, EH, MM; Methodology: MCDS, LG, AC, JPM, FG, EDG, RL, GS, SA, PD, CV, EG, VC, PEP, AM, EH and MM; Data curation: PD, CV and VCValidation: MCDS, EH and MM; Formal Analysis: MCDS, LG, AC, ER, JPM, FG, EM, NL, MB, RL, GS, SA, PD, CV, EG, VC, AM and MM. Investigation: MCDS, LG, AC, ER, JPM, FG, EM, NL, MB, RL, GS, SA, PD, CV, EG, VC, AM and MM. Resources: PDAC, FN, CV, EG, VC, AS; Writing-original draft preparation, MCDS, EH and MM; Visualisation: MCDS, EH, MM; Supervision: VC, AS, PEP, AM, EH, MM; Project Administration: MCDS, EH, MM; Funding Acquisition: EH, MM; Guarantor: MCDS, EH, MM.
Funding MCDS and JPM are supported by Fondazione Italiana per la Ricerca sul Cancro/Associazione Italiana Ricerca sul Cancro (FIRC/AIRC) fellowships (22 248 and 22558). FG is supported by Fondazione Pezcoller/SIC-Patrizia Coser. MM is supported by Worldwide Cancer Research grant (WWCR, 20–0033). EH is supported by AIRC (21875), MIUR (Ministero Università Ricerca, PRIN 2017) and Leducq Transatlantic Network of Excellence (19CVD02). EG is supported by AIRC (IG24444) and Dutch Cancer Society (KWF-11957). PD is supported by Fondazione Nadia Valsecchi Onlus. VC and AS are supported by AIRC (18 718 and 12182). AS is also supported by Italian Ministry of Health (FIMPDACUP_J38D19000690001). PEP is supported by AIRC (MFAG 2018 - ID. 21564). MB is supported by Fondazione Pezcoller/SIC Prof.ssa De Gasperi Ronc. AM is supported by AIRC and Fondazione Cassa di Risparmio di Firenze (IG22941 and MultiUser19515). FN is supported by AIRC (IG19931) and Fondazione Ricerca Molinette Onlus (Fondo CD38, Fondo Ursula and Giorgio Cytron). The data presented in the current study were in part generated using the equipment of the Facility di Medicina Molecolare, funded by 'Ministero dell’Istruzione dell’Università e della Ricerca-Bando Dipartimenti di Eccellenza 2018–2022' (AM).
Competing interests EH is a founder of Kither Biotech, a company involved in the development of PI3K inhibitors. The authors declare no potential conflicts of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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