Epco-53. multi-scale regulation of signaling cascades and tumor evolution in high grade astrocytomas

Abstract The National Cancer Institute Clinical Proteomic Atlas Consortium (CPTAC) herein reports our deep characterization of 228 grade IV IDH1 WT and mutant astrocytomas (including 28 matched primary and recurrent GBMs) using 15 proteogenomic and metabolomic platforms. Major advances over our first CPTAC GBM report (Wang et al., 2021, Cancer Cell), are the inclusion of many more samples including paired primary and recurrent tumors, application of new platforms, including glycoproteomics and targeted mass spectrometry methods, development and application of new computational techniques, and the integration of an atlas of experimentally determined, functional, kinase substrate interactions from Kinase Library. Paired primary-recurrent GBM analyses showed increased clonal diversity in recurrent tumors as a function of time, and treatment-induced mutation signatures. Proteomic and metabolomic analyses showed that different drivers can cause similar downstream effects. Only EGFR altered tumors were associated with dual EGFR glycosylation (N352 and N603) and EGFR phosphorylation (Y316) events. IDH1 mutation was associated with activated RTK signaling and decreased hypoxia pathway activities, concordant with epigenetic and metabolic profiles. Protein-protein interaction and kinase/phosphatase-substrate analyses uncovered detailed signaling events from different upstream drivers (e.g., EGFR, PDGFRA, and IDH1) converged through a PTPN11 hub to downstream effectors, including GAB1, IRS1, MAP3K5, and PTK2B. In summary, this multiscale resource presents new and deeper biological insights regarding treatment impact on tumor evolution, shared downstream consequences of independent drivers, and the potential importance of PTPN11 signaling circuitry across high-grade gliomas. We hope that reporting this new international resource to the SNO community will advance therapeutic development, including targeted therapies that may avoid known mechanisms of resistance.