Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities

• Published in: Nature communications Vol. 11; no. 1; p. 3288
• Main Authors: Oh, Sejin, Yeom, Jeonghun, Cho, Hee Jin, Kim, Ju-Hwa, Yoon, Seon-Jin, Kim, Hakhyun, Sa, Jason K., Ju, Shinyeong, Lee, Hwanho, Oh, Myung Joon, Lee, Wonyeop, Kwon, Yumi, Li, Honglan, Choi, Seunghyuk, Han, Jang Hee, Chang, Jong Hee, Choi, Eunsuk, Kim, Jayeon, Her, Nam-Gu, Kim, Se Hoon, Kang, Seok-Gu, Paek, Eunok, Nam, Do-Hyun, Lee, Cheolju, Kim, Hyun Seok
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.07.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 45; 45/23; 49; 631/1647/2067; 631/67/1922; 82/58; Biomarkers; Brain cancer; Brain tumors; Cytotoxicity; Dehydrogenase; Dehydrogenases; Glioblastoma; Glioma; Heterogeneity; Humanities and Social Sciences; Immune checkpoint; Isocitrate dehydrogenase; multidisciplinary; Oxidative phosphorylation; Peptidylprolyl isomerase; Pharmacology; Phosphoglycerate dehydrogenase; Phosphorylation; Prognosis; Science; Science (multidisciplinary); Stem cells; Subgroups; Tacrolimus-binding protein; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17139-y

The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 ( IDH ) wild-type glioblastoma (GBM) is currently limited due to high molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of IDH wild-type GBM tumors derived from a quantitative proteomic analysis of 39 IDH wild-type GBMs as well as IDH mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 ( FKBP9 ). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase ( PHGDH ). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies. The heterogeneity of IDH1/2 wild-type glioblastoma limits its prognosis and therapy. Here, the authors show a binary stratification, based on quantitative proteomic analysis of samples from patients with glioblastoma, with different prognosis and therapeutic vulnerabilities.