Targeting DNA-PK in cancer

被引：56

作者：

Damia, Giovanna ^{[1
]}

机构：

[1] Ist Ric Farmacol Mario Negri IRCCS, Dept Oncol, Lab Mol Pharmacol, Via Mario Negri 2, I-20156 Milan, Italy

来源：

MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS | 2020年 / 821卷

关键词：

DNA-PK; Small molecule inhibitor; DNA repair; Cancer; DEPENDENT PROTEIN-KINASE; STRAND BREAK REPAIR; HOMOLOGOUS RECOMBINATION; CATALYTIC SUBUNIT; DAMAGE RESPONSE; UP-REGULATION; ENHANCES CHEMOSENSITIVITY; IONIZING-RADIATION; CELLS; INHIBITORS;

D O I：

10.1016/j.mrfmmm.2020.111692

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

DNA-dependent protein kinase (DNA-PK) is involved in many cellular pathways. It has a key role in the cellular response to DNA damage, in the repair of DNA double-strand break (DNA-DSBs) and as a consequence an important role in maintaining genomic integrity. In addition, DNA-PK has been shown to modulate transcription, to be involved in the development of the immune system and to protect telomeres. These pleotropic involve-ments and the fact that its expression is de-regulated in cancer have made DNA-PK an intriguing therapeutic target in cancer therapy, especially when combined with agents causing DNA-DSBs such as topoisomerase II inhibitors and ionizing radiation. Different small molecule inhibitors of DNA-PK have been recently synthesized and some are now being tested in clinical trials. This review discusses what is known about DNA-PK, its role in tumor biology, DNA repair and cancer therapy and critically discusses its inhibition as a potential therapeutic approach.

引用

页数：7

共 105 条

[1] ATM, ATR and DNA-PKcs expressions correlate to adverse clinical outcomes in epithelial ovarian cancers [J].

Abdel-Fatah, Tarek M. A. ;

Arora, Arvind ;

Moseley, Paul ;

Coveney, Clare ;

Perry, Christina ;

Johnson, Kerstie ;

Kent, Christopher ;

Ball, Graham ;

Chan, Stephen ;

Madhusudan, Srinivasan .

BBA CLINICAL, 2014, 2 :10-17

[2] Inhibition of DNA-PK enhances chemosensitivity of B-cell precursor acute lymphoblastic leukemia cells to doxorubicin [J].

Alikarami, Fatemeh ;

Safa, Majid ;

Faranoush, Mohammad ;

Hayat, Parisa ;

Kazemi, Ahmad .

BIOMEDICINE & PHARMACOTHERAPY, 2017, 94 :1077-1093

[3] Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System [J].

Alt, Frederick W. ;

Zhang, Yu ;

Meng, Fei-Long ;

Guo, Chunguang ;

Schwer, Bjoern .

CELL, 2013, 152 (03) :417-429

[4]

[Anonymous], CANCER RES S14

[5]

[Anonymous], 2016, CANC RES S, V77

[6] Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases [J].

Apsel, Beth ;

Blair, Jimmy A. ;

Gonzalez, Beatriz ;

Nazif, Tamim M. ;

Feldman, Morri E. ;

Aizenstein, Brian ;

Hoffman, Randy ;

Williams, Roger L. ;

Shokat, Kevan M. ;

Knight, Zachary A. .

NATURE CHEMICAL BIOLOGY, 2008, 4 (11) :691-699

[7] Reduced DNA-dependent protein kinase activity is associated with lung cancer [J].

Auckley, DH ;

Crowell, RE ;

Heaphy, ER ;

Stidley, CA ;

Lechner, JF ;

Gilliland, FD ;

Belinsky, SA .

CARCINOGENESIS, 2001, 22 (05) :723-727

[8]

Belenkov AI, 2002, CANCER RES, V62, P5888

[9] A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer [J].

Bendell, Johanna C. ;

Varghese, Anna M. ;

Hyman, David M. ;

Bauer, Todd M. ;

Pant, Shubham ;

Callies, Sophie ;

Lin, Ji ;

Martinez, Ricardo ;

Wickremsinhe, Enaksha ;

Fink, Aaron ;

Wacheck, Volker ;

Moore, Kathleen N. .

CLINICAL CANCER RESEARCH, 2018, 24 (14) :3253-3262

[10] Radioresistant cervical cancer shows upregulation of the NHEJ proteins DNA-PKcs, Ku70 and Ku86 [J].

Beskow, C. ;

Skikuniene, J. ;

Holgersson, A. ;

Nilsson, B. ;

Lewensohn, R. ;

Kanter, L. ;

Viktorsson, K. .

BRITISH JOURNAL OF CANCER, 2009, 101 (05) :816-821

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