American Association for Cancer Research
15357163mct200981-sup-255608_2_supp_7328459_qxx8ny.xlsx (182.12 kB)

Supplementary Table 2 from Phosphoproteomics Identifies PI3K Inhibitor–selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance

Download (182.12 kB)
posted on 2023-04-03, 18:46 authored by Célia Cintas, Thibault Douche, Zahra Dantes, Emmanuelle Mouton-Barbosa, Marie-Pierre Bousquet, Coralie Cayron, Nicole Therville, Frédéric Pont, Fernanda Ramos-Delgado, Camille Guyon, Barbara Garmy-Susini, Paola Cappello, Odile Burlet-Schiltz, Emilio Hirsch, Anne Gomez-Brouchet, Benoît Thibault, Maximilian Reichert, Julie Guillermet-Guibert

Supplementary Table 2 contains the list of isoform selective peptides in each condition, with quantification and global pathway analysis.



Université de Toulouse

Ligue Nationale Contre le Cancer

Fondation pour la recherche Médicale FRM

Fondation FONROGA

Fondation de France



Université Paul Sabatier for French-German student exchange

German Research Foundation

German Cancer Aid Foundation

Région Midi-Pyrénées, European funds

French Ministry of Research



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 be 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 PI3Kα, PI3Kβ, or PI3Kγ (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 α-selective BYL-719 with γ-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.