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

Nat Commun. 2020 Jul 3;11(1):3288. doi: 10.1038/s41467-020-17139-y.

Sejin Oh ^# ¹ ², Jeonghun Yeom ^# ³ ⁴ ⁵, Hee Jin Cho ^# ⁶ ⁷, Ju-Hwa Kim ⁸, Seon-Jin Yoon ² ⁹, Hakhyun Kim ², Jason K Sa ¹⁰, Shinyeong Ju ³ ¹¹, Hwanho Lee ² ¹², Myung Joon Oh ¹, Wonyeop Lee ¹³, Yumi Kwon ³ ¹¹, Honglan Li ¹³ ¹⁴, Seunghyuk Choi ¹³, Jang Hee Han ¹ ¹⁵, Jong Hee Chang ¹⁶, Eunsuk Choi ⁶ ¹⁷, Jayeon Kim ⁶ ⁷, Nam-Gu Her ⁶, Se Hoon Kim ¹⁸, Seok-Gu Kang ¹⁵ ¹⁶, Eunok Paek ¹⁹, Do-Hyun Nam ²⁰ ²¹ ²², Cheolju Lee ²³ ²⁴ ²⁵, Hyun Seok Kim ²⁶ ²⁷

Affiliations

1 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
2 Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
3 Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea.
4 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Korea.
5 Convergence Medicine Research Center, Asan Institute for Life Sciences, Seoul, Korea.
6 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea.
7 Precision Medicine Research Institute, Samsung Medical Center, Seoul, Korea.
8 Graduate Program for Nanomedical Science, Yonsei University, Seoul, Korea.
9 Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Korea.
10 Department of Biomedical Sciences, Korea University College of Medicine, Seoul, Korea.
11 Department of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul, Korea.
12 Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
13 Department of Computer Science, Hanyang University, Seoul, Korea.
14 School of Computer Science and Engineering, Soongsil University, Seoul, Korea.
15 Department of Medical Science, Yonsei University Graduate School, Seoul, Korea.
16 Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
17 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
18 Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.
19 Department of Computer Science, Hanyang University, Seoul, Korea. eunokpaek@hanyang.ac.kr.
20 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea. nsnam@skku.edu.
21 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. nsnam@skku.edu.
22 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. nsnam@skku.edu.
23 Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea. clee270@kist.re.kr.
24 Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Korea. clee270@kist.re.kr.
25 Department of Converging Science and Technology, KHU-KIST, Kyung Hee University, Seoul, Korea. clee270@kist.re.kr.
26 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. hsfkim@yuhs.ac.
27 Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. hsfkim@yuhs.ac.
# Contributed equally.

PMID: 32620753 DOI: 10.1038/s41467-020-17139-y

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-117240

NCT-502

99.72%, PHGDH Inhibitor

Phosphoglycerate Dehydrogenase (PHGDH)

Cancer

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