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.

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.

Details

Title
Integrated pharmaco-proteogenomics defines two subgroups in isocitrate dehydrogenase wild-type glioblastoma with prognostic and therapeutic opportunities
Author
Oh Sejin 1   VIAFID ORCID Logo  ; Yeom Jeonghun 2   VIAFID ORCID Logo  ; Cho Hee Jin 3 ; Ju-Hwa, Kim 4 ; Seon-Jin, Yoon 5   VIAFID ORCID Logo  ; Kim Hakhyun 6   VIAFID ORCID Logo  ; Sa, Jason K 7   VIAFID ORCID Logo  ; Ju Shinyeong 8   VIAFID ORCID Logo  ; Lee, Hwanho 9   VIAFID ORCID Logo  ; Oh, Myung Joon 10 ; Lee, Wonyeop 11 ; Kwon Yumi 8 ; Li, Honglan 12 ; Choi Seunghyuk 11   VIAFID ORCID Logo  ; Han, Jang Hee 13 ; Chang, Jong Hee 14   VIAFID ORCID Logo  ; Choi Eunsuk 15   VIAFID ORCID Logo  ; Kim Jayeon 3 ; Nam-Gu, Her 16 ; Kim, Se Hoon 17   VIAFID ORCID Logo  ; Seok-Gu, Kang 18   VIAFID ORCID Logo  ; Paek Eunok 11   VIAFID ORCID Logo  ; Do-Hyun, Nam 19 ; Lee, Cheolju 20   VIAFID ORCID Logo  ; Kim, Hyun Seok 1   VIAFID ORCID Logo 

1  Yonsei University College of Medicine, Severance Biomedical Science Institute, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Yonsei University College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
2  Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea (GRID:grid.35541.36) (ISNI:0000000121053345); Korea University of Science and Technology, Division of Bio-Medical Science & Technology, KIST School, Seoul, Korea (GRID:grid.412786.e) (ISNI:0000 0004 1791 8264); Convergence Medicine Research Center, Asan Institute for Life Sciences, Seoul, Korea (GRID:grid.413967.e) (ISNI:0000 0001 0842 2126) 
3  Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea (GRID:grid.414964.a) (ISNI:0000 0001 0640 5613); Precision Medicine Research Institute, Samsung Medical Center, Seoul, Korea (GRID:grid.414964.a) (ISNI:0000 0001 0640 5613) 
4  Yonsei University, Graduate Program for Nanomedical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
5  Yonsei University College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Yonsei University College of Medicine, Department of Biochemistry and Molecular Biology, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
6  Yonsei University College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
7  Korea University College of Medicine, Department of Biomedical Sciences, Seoul, Korea (GRID:grid.222754.4) (ISNI:0000 0001 0840 2678) 
8  Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea (GRID:grid.35541.36) (ISNI:0000000121053345); Hanyang University, Department of Life Science and Research Institute for Natural Sciences, Seoul, Korea (GRID:grid.49606.3d) (ISNI:0000 0001 1364 9317) 
9  Yonsei University College of Medicine, Brain Korea 21 PLUS Project for Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Yonsei University, Department of Systems Biology, College of Life Science and Biotechnology, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
10  Yonsei University College of Medicine, Severance Biomedical Science Institute, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
11  Hanyang University, Department of Computer Science, Seoul, Korea (GRID:grid.49606.3d) (ISNI:0000 0001 1364 9317) 
12  Hanyang University, Department of Computer Science, Seoul, Korea (GRID:grid.49606.3d) (ISNI:0000 0001 1364 9317); Soongsil University, School of Computer Science and Engineering, Seoul, Korea (GRID:grid.263765.3) (ISNI:0000 0004 0533 3568) 
13  Yonsei University College of Medicine, Severance Biomedical Science Institute, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Yonsei University Graduate School, Department of Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
14  Yonsei University College of Medicine, Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
15  Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea (GRID:grid.414964.a) (ISNI:0000 0001 0640 5613); Sungkyunkwan University School of Medicine, Department of Neurosurgery, Samsung Medical Center, Seoul, Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X) 
16  Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea (GRID:grid.414964.a) (ISNI:0000 0001 0640 5613) 
17  Yonsei University College of Medicine, Department of Pathology, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
18  Yonsei University Graduate School, Department of Medical Science, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454); Yonsei University College of Medicine, Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Seoul, Korea (GRID:grid.15444.30) (ISNI:0000 0004 0470 5454) 
19  Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea (GRID:grid.414964.a) (ISNI:0000 0001 0640 5613); Sungkyunkwan University School of Medicine, Department of Neurosurgery, Samsung Medical Center, Seoul, Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X); SAIHST, Sungkyunkwan University, Department of Health Sciences and Technology, Seoul, Korea (GRID:grid.264381.a) (ISNI:0000 0001 2181 989X) 
20  Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea (GRID:grid.35541.36) (ISNI:0000000121053345); Korea University of Science and Technology, Division of Bio-Medical Science & Technology, KIST School, Seoul, Korea (GRID:grid.412786.e) (ISNI:0000 0004 1791 8264); KHU-KIST, Kyung Hee University, Department of Converging Science and Technology, Seoul, Korea (GRID:grid.289247.2) (ISNI:0000 0001 2171 7818) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-17139-y
ProQuest document ID
2419781593
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.