Phosphoproteomics Identifies PI3K Inhibitor-selective Adaptive Responses in Pancreatic Cancer Cell Therapy and Resistance.

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, PI3Kß, 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.

Interpersonal brain synchronization with instructor compensates for learner's sleep deprivation in interactive learning.

Recent advances shifted the focus on single-brain functioning toward two-brain communication during learning interactions, following the demonstration that interpersonal brain synchronization (IBS) can track instructor-learner information exchange. Here, we investigated (i) whether sleep deprivation (SD) that potentially impacts both social interactions and learning abilities modulates IBS, and (ii) conversely whether and to what extent IBS might compensate for SD-related learning deficits. Instructors (always with regular sleep, RS) were asked to teach numerical reasoning strategies to learners (either SD or RS), during which the activity of both brains was simultaneously recorded using functional near-infrared spectroscopy (fNIRS). SD learners initially performed below their baseline level, worse than RS learners, but learning improvement was comparable between RS and SD conditions after learning with the instructor. IBS within the instructor-learner dyads was higher in the SD (vs. RS) condition in the left inferior frontal cortex. In addition, clustered IBS (estimated by nonnegative matrix factorization) was correlated with performance improvement. Finally, Granger Causality analyses revealed biased causality with higher instructor-to-learner than learner-to-instructor directionality in brain signal processing. Together, these results indicate that SD-related learning deficits can to some extent be compensated via interactions with an instructor, as reflected by increased IBS and preserved learning ability. It suggests an essential role of the instructor in driving synchrony between teaching and SD learning brains during interactions.