한빛사논문
- 조회431
Yoonhee Nam1†, Harim Koo2,3,4,5†, Yingxi Yang6†, Sang Shin2†, Zhihan Zhu6, Donggeon Kim2, Hee Jin Cho7,8, Quanhua Mu6, Seung Won Choi9, Jason K. Sa3, Yun Jee Seo2, Yejin Kim2, Kyoungmin Lee2, Jeong‑Woo Oh2, Yong‑Jun Kwon2, Woong‑Yang Park10,11, Doo‑Sik Kong12, Ho Jun Seol12, Jung‑Il Lee12, Chul‑Kee Park13, Hye Won Lee14,15*, Yeup Yoon2,10,16* and Jiguang Wang1,6,17,18
1Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China.
2Institute for Refractory Cancer Research, Research Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
3Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.
4Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, South Korea.
5Department of Clinical Research, Research Institute and Hospital, National Cancer Center, Goyang, South Korea.
6Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China.
7Department of Biomedical Convergence Science and Technology, School of Convergence, Kyungpook National University, Daegu, South Korea.
8Cell and Matrix Research Institute, Kyungpook National University, Daegu, South Korea.
9Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA.
10Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea.
11Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
12Department of Neurosurgery, Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul, South Korea.
13Department of Neurosurgery, College of Medicine, Seoul National University and Seoul National University Hospital, Seoul, South Korea.
14Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang, South Korea.
15Department of Urology, Samsung Medical Center, Seoul, South Korea.
16Department of Biopharmaceutical Convergence, Sungkyunkwan University, Seoul, South Korea.
17Hong Kong Center for Neurodegenerative Diseases, InnoHK, Hong Kong SAR, China.
18HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, China.
†Yoonhee Nam, Harim Koo, Yingxi Yang, and Sang Shin contributed equally.
*Correspondence: Hye Won Lee, Yeup Yoon, Jiguang Wang
Abstract
Background: Although temozolomide (TMZ) has been used as a standard adjuvant chemotherapeutic agent for primary glioblastoma (GBM), treating isocitrate dehydrogenase wild-type (IDH-wt) cases remains challenging due to intrinsic and acquired drug resistance. Therefore, elucidation of the molecular mechanisms of TMZ resistance is critical for its precision application.
Methods: We stratified 69 primary IDH-wt GBM patients into TMZ-resistant (n = 29) and sensitive (n = 40) groups, using TMZ screening of the corresponding patient-derived glioma stem-like cells (GSCs). Genomic and transcriptomic features were then examined to identify TMZ-associated molecular alterations. Subsequently, we developed a machine learning (ML) model to predict TMZ response from combined signatures. Moreover, TMZ response in multisector samples (52 tumor sectors from 18 cases) was evaluated to validate findings and investigate the impact of intra-tumoral heterogeneity on TMZ efficacy.
Results: In vitro TMZ sensitivity of patient-derived GSCs classified patients into groups with different survival outcomes (P = 1.12e-4 for progression-free survival (PFS) and 3.63e-4 for overall survival (OS)). Moreover, we found that elevated gene expression of EGR4, PAPPA, LRRC3, and ANXA3 was associated to intrinsic TMZ resistance. In addition, other features such as 5-aminolevulinic acid negative, mesenchymal/proneural expression subtypes, and hypermutation phenomena were prone to promote TMZ resistance. In contrast, concurrent copy-number-alteration in PTEN, EGFR, and CDKN2A/B was more frequent in TMZ-sensitive samples (Fisher's exact P = 0.0102), subsequently consolidated by multi-sector sequencing analyses. Integrating all features, we trained a ML tool to segregate TMZ-resistant and sensitive groups. Notably, our method segregated IDH-wt GBM patients from The Cancer Genome Atlas (TCGA) into two groups with divergent survival outcomes (P = 4.58e-4 for PFS and 3.66e-4 for OS). Furthermore, we showed a highly heterogeneous TMZ-response pattern within each GBM patient using in vitro TMZ screening and genomic characterization of multisector GSCs. Lastly, the prediction model that evaluates the TMZ efficacy for primary IDH-wt GBMs was developed into a webserver for public usage ( http://www.wang-lab-hkust.com:3838/TMZEP ).
Conclusions: We identified molecular characteristics associated to TMZ sensitivity, and illustrate the potential clinical value of a ML model trained from pharmacogenomic profiling of patient-derived GSC against IDH-wt GBMs.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-15)
- 국내(교신)+국외 연구진
- 의약학 > 응용의학
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