Therapeutic targeting of the MYC signal by inhibition of histone chaperone FACT in neuroblastoma

被引：112

作者：

Carter, Daniel R. ^{[1
,2
]}

Murray, Jayne ^{[1
]}

Cheung, Belamy B. ^{[1
,2
]}

Gamble, Laura ^{[1
]}

Koach, Jessica ^{[1
]}

Tsang, Joanna ^{[1
]}

Sutton, Selina ^{[1
]}

Kalla, Heyam ^{[1
]}

Syed, Sarah ^{[1
]}

Gifford, Andrew J. ^{[1
,3
]}

Issaeva, Natalia ^{[4
,5
]}

Biktasova, Asel ^{[4
,5
]}

Atmadibrata, Bernard ^{[1
]}

Sun, Yuting ^{[1
]}

Sokolowski, Nicolas ^{[1
]}

Ling, Dora ^{[1
]}

Kim, Patrick Y. ^{[1
]}

Webber, Hannah ^{[1
]}

Clark, Ashleigh ^{[1
]}

Ruhle, Michelle ^{[1
]}

Liu, Bing ^{[1
]}

Oberthuer, Andre ^{[6
,7
]}

Fischer, Matthias ^{[6
,8
]}

Byrne, Jennifer ^{[9
,10
]}

Saletta, Federica ^{[9
]}

Thwe, Le Myo ^{[9
,10
]}

Purmal, Andrei ^{[11
]}

Haderski, Gary ^{[12
]}

Burkhart, Catherine ^{[12
]}

Speleman, Frank ^{[13
]}

De Preter, Katleen ^{[13
]}

Beckers, Anneleen ^{[13
]}

Ziegler, David S. ^{[1
,2
,14
]}

Liu, Tao ^{[13
]}

Gurova, Katerina V. ^{[11
,15
]}

Gudkov, Andrei V. ^{[11
,15
]}

Norris, Murray D. ^{[1
,16
]}

Haber, Michelle ^{[1
]}

Marshall, Glenn M. ^{[1
,14
]}

机构：

[1] Univ New S Wales, Lowy Canc Res Ctr, Childrens Canc Inst Australia, Randwick, NSW 2031, Australia

[2] UNSW Australia, Sch Womens & Childrens Hlth, Randwick, NSW 2031, Australia

[3] Prince Wales Hosp, Dept Anat Pathol SEALS, Randwick, NSW 2031, Australia

[4] Yale Univ, Dept Surg, Otolaryngol, New Haven, CT 06511 USA

[5] Yale Univ, Yale Canc Ctr, New Haven, CT 06511 USA

[6] Univ Cologne, Childrens Hosp, Dept Pediat Oncol & Hematol, D-50931 Cologne, Germany

[7] Univ Cologne, Childrens Hosp, Dept Neonatol & Pediat Intens Care Med, D-50931 Cologne, Germany

[8] Max Planck Inst Metab Res, D-50931 Cologne, Germany

[9] Childrens Hosp Westmead, Kids Res Inst, Childrens Canc Res Unit, Westmead, NSW 2145, Australia

[10] Univ Sydney, Discipline Paediat & Child Hlth, Childrens Hosp Westmead, Westmead, NSW 2145, Australia

[11] Incuron LLC, Buffalo, NY 14203 USA

[12] Buffalo BioLabs LLC, Buffalo, NY 14203 USA

[13] Univ Ghent, Ctr Med Genet CMGG, B-9000 Ghent, Belgium

[14] Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW 2031, Australia

[15] Roswell Pk Canc Inst, Dept Cell Stress Biol, Buffalo, NY 14263 USA

[16] Univ New S Wales, Ctr Childhood Canc Res, Randwick, NSW 2031, Australia

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2015年 / 7卷 / 312期

基金：

英国医学研究理事会;

关键词：

CHROMATIN TRANSCRIPTION FACT; BET BROMODOMAIN INHIBITION; SPONTANEOUS REGRESSION; MALIGNANT PROGRESSION; TUMOR INITIATION; IN-VIVO; CANCER; P53; EXPRESSION; PROTEIN;

D O I：

10.1126/scitranslmed.aab1803

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease. FACT and MYCN expression created a forward feedback loop in neuroblastoma cells that was essential for maintaining mutual high expression. FACT inhibition by the small-molecule curaxin compound CBL0137 markedly reduced tumor initiation and progression in vivo. CBL0137 exhibited strong synergy with standard chemotherapy by blocking repair of DNA damage caused by genotoxic drugs, thus creating a synthetic lethal environment in MYCN-amplified neuroblastoma cells and suggesting a treatment strategy for MYCN-driven neuroblastoma.

引用

页数：12

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