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

Sejin Oh, Jeonghun Yeom, Hee Jin Cho, Ju Hwa Kim, Seon Jin Yoon, Hakhyun Kim, Jason K. Sa, Shinyeong Ju, Hwanho Lee, Myung Joon Oh, Wonyeop Lee, Yumi Kwon, Honglan Li, Seunghyuk Choi, Jang Hee Han, Jong Hee Chang, Eunsuk Choi, Jayeon Kim, Nam Gu Her, Se Hoon KimSeok Gu Kang, Eunok Paek, Do Hyun Nam, Cheolju Lee, Hyun Seok Kim

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number3288
JournalNature communications
Volume11
Issue number1
DOIs
Publication statusPublished - 2020 Dec 1

Bibliographical note

Funding Information:
We thank Sang Bum Kim and Daniel H. Kim for critical reading of the manuscript and their helpful discussions. The biospecimens for this study were provided by the Samsung Medical Center BioBank. This study was supported by grants from the National Research Foundation of Korea (2020R1A2C3007792, 2017M3A9F9030559, 2017M3C9A5031595, 2012M3A9B9036676, 2017R1E1A1A01077412, 2019R1A2C3004155, and 2019H1A2A1075632) and the Korea Health Technology R&D project through the Korea Health Industry Development Institute (HI14C1324, HI14C3418).

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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