期刊
MOLECULAR CANCER THERAPEUTICS
卷 20, 期 12, 页码 2433-2445出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-20-0981
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类别
资金
- RITC
- Universite de Toulouse
- Ligue Nationale Contre le Cancer
- Fondation pour la Recherche Medicale FRM
- Inca
- Fondation FONROGA
- Fondation de France
- MSCA-ITN-PhD
- COST PanGenEU
- Universite Paul Sabatier for French-German student exchange
- German Research Foundation (Deutsche Forschungsgemeinschaft) [SFB1321, 329628492, RE 3723/4-1]
- Region Midi-Pyrenees
- European funds (Fonds Europeens de Developpement Regional, FEDER)
- Toulouse Metropole
- French Ministry of Research with the Investissement d'Avenir Infrastructures Nationales en Biologie et Sante program (ProFI, Proteomics French Infrastructure project) [ANR-10-INBS-08]
- Forcheur Jean-Marie Lehn Award
- GermanCancer Aid Foundation (Max Eder Program,DeutscheKrebshilfe) [111273]
The PI3K pathway is highly active in human cancers and its inhibition is a potential therapeutic strategy for pancreatic cancer. However, different isoform-selective PI3K inhibitors have varying effects, with some leading to reactivation of downstream signaling. Combining inhibitors with different isoform selectivity may prevent the induction of compensatory signals and have a synergistic effect on cell survival.
The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to he responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3K alpha, PI3K beta, or PI3K gamma (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved a-selective BYL-719 with gamma-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.
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