Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor

被引：313

作者：

Hu, Huimin ^{[1
]}

Mu, Quanhua ^{[2
,12
]}

Bao, Zhaoshi ^{[1
,4
]}

Chen, Yiyun ^{[3
,12
]}

Liu, Yanwei ^{[1
,5
]}

Chen, Jing ^{[1
]}

Wang, Kuanyu ^{[1
]}

Wang, Zheng ^{[1
]}

Nam, Yoonhee ^{[3
]}

Jiang, Biaobin ^{[2
,3
,13
]}

Sa, Jason K. ^{[10
]}

Cho, Hee-Jin ^{[10
]}

Her, Nam-Gu ^{[10
]}

Zhang, Chuanbao ^{[4
]}

Zhao, Zheng ^{[1
]}

Zhang, Ying ^{[1
]}

Zeng, Fan ^{[1
]}

Wu, Fan ^{[1
]}

Kang, Xun ^{[6
]}

Liu, Yuqing ^{[1
]}

Qian, Zenghui ^{[1
]}

Wang, Zhiliang ^{[1
]}

Huang, Ruoyu ^{[1
]}

Wang, Qiangwei ^{[1
]}

Zhang, Wei ^{[4
]}

Qiu, Xiaoguang ^{[5
]}

Li, Wenbin ^{[6
]}

Nam, Do-Hyun ^{[10
,11
]}

Fan, Xiaolong ^{[7
]}

Wang, Jiguang ^{[2
,3
,12
]}

Jiang, Tao ^{[1
,4
,8
,9
]}

机构：

[1] Capital Med Univ, Beijing Neurosurg Inst, Beijing 100050, Peoples R China

[2] Hong Kong Univ Sci & Technol, Dept Chem & Biol Engn, Hong Kong, Hong Kong, Peoples R China

[3] Hong Kong Univ Sci & Technol, Div Life Sci, Hong Kong, Hong Kong, Peoples R China

[4] Capital Med Univ, Beijing Tiantan Hosp, Dept Neurosurg, Beijing 100050, Peoples R China

[5] Capital Med Univ, Beijing Tiantan Hosp, Dept Radiotherapy, Beijing 100050, Peoples R China

[6] Capital Med Univ, Beijing Shijitan Hosp, Dept Oncol, Beijing 100050, Peoples R China

[7] Beijing Normal Univ, Lab Neurosci & Brain Dev, Beijing Key Lab Gene Resource & Mol Dev, Beijing 100875, Peoples R China

[8] Beijing Inst Brain Disorders, Ctr Brain Tumor, Beijing 100069, Peoples R China

[9] China Natl Clin Res Ctr Neurol Dis, Beijing 100050, Peoples R China

[10] Samsung Med Ctr, Inst Refractory Canc Res, Seoul, South Korea

[11] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Neurosurg, Seoul, South Korea

[12] Hong Kong Univ Sci & Technol, Ctr Syst Biol & Human Hlth, Hong Kong, Hong Kong, Peoples R China

[13] Hong Kong Univ Sci & Technol, Inst Adv Study, Hong Kong, Hong Kong, Peoples R China

来源：

CELL | 2018年 / 175卷 / 06期

基金：

中国国家自然科学基金;

关键词：

RNA-SEQ; GENOMIC CHARACTERIZATION; REVEALS; EVOLUTION; GLIOMAS; GENE; CHEMORESISTANCE; ARCHITECTURE; PROGRESSION; ACTIVATION;

D O I：

10.1016/j.cell.2018.09.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in similar to 14% of cases with significantly worse prognosis Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in pre-clinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

引用

页码：1665 / +

页数：32

共 50 条

[31] The protein kinase complement of the human genome [J].

Manning, G ;

Whyte, DB ;

Martinez, R ;

Hunter, T ;

Sudarsanam, S .

SCIENCE, 2002, 298 (5600) :1912-+

[32] Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1 [J].

Mazor, Tali ;

Chesnelong, Charles ;

Pankov, Aleksandr ;

Jalbert, Llewellyn E. ;

Hong, Chibo ;

Hayes, Josie ;

Smirnov, Ivan V. ;

Marshall, Roxanne ;

Souza, Camila F. ;

Shen, Yaoqing ;

Viswanath, Pavithra ;

Noushmehr, Houtan ;

Ronen, Sabrina M. ;

Jones, Steven J. M. ;

Marra, Marco A. ;

Cairncross, J. Gregory ;

Perry, Arie ;

Nelson, Sarah J. ;

Chang, Susan M. ;

Bollen, Andrew W. ;

Molinaro, Annette M. ;

Bengtsson, Henrik ;

Olshen, Adam B. ;

Weiss, Samuel ;

Phillips, Joanna J. ;

Luchman, H. Artee ;

Costello, Joseph F. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2017, 114 (40) :10743-10748

[33] DNA Methylation and Somatic Mutations Converge on the Cell Cycle and Define Similar Evolutionary Histories in Brain Tumors [J].

Mazor, Tali ;

Pankov, Aleksandr ;

Johnson, Brett E. ;

Hong, Chibo ;

Hamilton, Emily G. ;

Bell, Robert J. A. ;

Smirnov, Ivan V. ;

Reis, Gerald F. ;

Phillips, Joanna J. ;

Barnes, Michael J. ;

Idbaih, Ahmed ;

Alentorn, Agusti ;

Kloezeman, Jenneke J. ;

Lamfers, Martine L. M. ;

Bollen, Andrew W. ;

Taylor, Barry S. ;

Molinaro, Annette M. ;

Olshen, Adam B. ;

Chang, Susan M. ;

Song, Jun S. ;

Costello, Joseph F. .

CANCER CELL, 2015, 28 (03) :307-317

[34]

Newman AM, 2015, NAT METHODS, V12, P453, DOI [10.1038/nmeth.3337, 10.1038/NMETH.3337]

[35] IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas [J].

Nobusawa, Sumihito ;

Watanabe, Takuya ;

Kleihues, Paul ;

Ohgaki, Hiroko .

CLINICAL CANCER RESEARCH, 2009, 15 (19) :6002-6007

[36] The Definition of Primary and Secondary Glioblastoma [J].

Ohgaki, Hiroko ;

Kleihues, Paul .

CLINICAL CANCER RESEARCH, 2013, 19 (04) :764-772

[37] An integrated genomic analysis of human glioblastoma Multiforme [J].

Parsons, D. Williams ;

Jones, Sian ;

Zhang, Xiaosong ;

Lin, Jimmy Cheng-Ho ;

Leary, Rebecca J. ;

Angenendt, Philipp ;

Mankoo, Parminder ;

Carter, Hannah ;

Siu, I-Mei ;

Gallia, Gary L. ;

Olivi, Alessandro ;

McLendon, Roger ;

Rasheed, B. Ahmed ;

Keir, Stephen ;

Nikolskaya, Tatiana ;

Nikolsky, Yuri ;

Busam, Dana A. ;

Tekleab, Hanna ;

Diaz, Luis A., Jr. ;

Hartigan, James ;

Smith, Doug R. ;

Strausberg, Robert L. ;

Marie, Suely Kazue Nagahashi ;

Shinjo, Sueli Mieko Oba ;

Yan, Hai ;

Riggins, Gregory J. ;

Bigner, Darell D. ;

Karchin, Rachel ;

Papadopoulos, Nick ;

Parmigiani, Giovanni ;

Vogelstein, Bert ;

Velculescu, Victor E. ;

Kinzler, Kenneth W. .

SCIENCE, 2008, 321 (5897) :1807-1812

[38] Targeting cellular pathways in glioblastoma multiforme [J].

Pearson, Joshua R. D. ;

Regad, Tarik .

SIGNAL TRANSDUCTION AND TARGETED THERAPY, 2017, 2

[39] Integrative genomics viewer [J].

Robinson, James T. ;

Thorvaldsdottir, Helga ;

Winckler, Wendy ;

Guttman, Mitchell ;

Lander, Eric S. ;

Getz, Gad ;

Mesirov, Jill P. .

NATURE BIOTECHNOLOGY, 2011, 29 (01) :24-26

[40] dbSNP: the NCBI database of genetic variation [J].

Sherry, ST ;

Ward, MH ;

Kholodov, M ;

Baker, J ;

Phan, L ;

Smigielski, EM ;

Sirotkin, K .

NUCLEIC ACIDS RESEARCH, 2001, 29 (01) :308-311

← 1 2 3 4 5 →