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

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

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.

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