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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 Kim  ;  Seok-Gu Kang  ;  Eunok Paek  ;  Do-Hyun Nam  ;  Cheolju Lee  ;  Hyun Seok Kim 
 NATURE COMMUNICATIONS, Vol.11(1) : 3288, 2020-07 
Journal Title
Issue Date
Benzamides / pharmacology ; Biomarkers, Tumor / genetics ; Biomarkers, Tumor / metabolism* ; Brain Neoplasms / genetics ; Brain Neoplasms / metabolism* ; Brain Neoplasms / therapy ; Cell Line, Tumor ; Cell Survival / drug effects ; Cell Survival / genetics ; Glioblastoma / genetics ; Glioblastoma / metabolism* ; Glioblastoma / therapy ; Humans ; Isocitrate Dehydrogenase / classification ; Isocitrate Dehydrogenase / genetics* ; Isocitrate Dehydrogenase / metabolism ; Kaplan-Meier Estimate ; Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 1 / metabolism ; Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors ; Mechanistic Target of Rapamycin Complex 2 / metabolism ; Morpholines / pharmacology ; Mutation ; Prognosis ; Protein Kinase Inhibitors / pharmacology ; Proteogenomics / methods* ; Proteomics / methods* ; Pyrimidines / pharmacology
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Biomedical Systems Informatics (의생명시스템정보학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
Oh, Se Jin(오세진)
Yoon, Seon Jin(윤선진) ORCID logo https://orcid.org/0000-0002-3255-5081
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
Han, Jang Hee(한장희)
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