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 () and Hyun Seok Kim ()
Additional contact information
Sejin Oh: Yonsei University College of Medicine
Jeonghun Yeom: Center for Theragnosis, Korea Institute of Science and Technology
Hee Jin Cho: Institute for Refractory Cancer Research, Samsung Medical Center
Ju-Hwa Kim: Yonsei University
Seon-Jin Yoon: Yonsei University College of Medicine
Hakhyun Kim: Yonsei University College of Medicine
Jason K. Sa: Korea University College of Medicine
Shinyeong Ju: Center for Theragnosis, Korea Institute of Science and Technology
Hwanho Lee: Yonsei University College of Medicine
Myung Joon Oh: Yonsei University College of Medicine
Wonyeop Lee: Hanyang University
Yumi Kwon: Center for Theragnosis, Korea Institute of Science and Technology
Honglan Li: Hanyang University
Seunghyuk Choi: Hanyang University
Jang Hee Han: Yonsei University College of Medicine
Jong Hee Chang: Yonsei University College of Medicine
Eunsuk Choi: Institute for Refractory Cancer Research, Samsung Medical Center
Jayeon Kim: Institute for Refractory Cancer Research, Samsung Medical Center
Nam-Gu Her: Institute for Refractory Cancer Research, Samsung Medical Center
Se Hoon Kim: Yonsei University College of Medicine
Seok-Gu Kang: Yonsei University Graduate School
Eunok Paek: Hanyang University
Do-Hyun Nam: Institute for Refractory Cancer Research, Samsung Medical Center
Cheolju Lee: Center for Theragnosis, Korea Institute of Science and Technology
Hyun Seok Kim: Yonsei University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17139-y

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