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. [email protected].
  • 20. Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea. [email protected].
  • 21. Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. [email protected].
  • 22. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. [email protected].
  • 23. Center for Theragnosis, Korea Institute of Science and Technology, Seoul, Korea. [email protected].
  • 24. Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, Korea. [email protected].
  • 25. Department of Converging Science and Technology, KHU-KIST, Kyung Hee University, Seoul, Korea. [email protected].
  • 26. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea. [email protected].
  • 27. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. [email protected].
  • # 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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