Chemosensitive Relapse in Small Cell Lung Cancer Proceeds through an EZH2-SLFN11 Axis

被引：430

作者：

Gardner, Eric E. ^{[1
,2
]}

Lok, Benjamin H. ^{[2
,3
]}

Schneeberger, Valentina E. ^{[2
]}

Desmeules, Patrice ^{[4
]}

Miles, Linde A. ^{[2
]}

Arnold, Paige K. ^{[5
]}

Ni, Andy ^{[6
]}

Khodos, Inna ^{[7
]}

de Stanchina, Elisa ^{[2
,7
]}

Thuyen Nguyen ^{[8
,9
]}

Sage, Julien ^{[8
,9
]}

Campbell, John E. ^{[10
]}

Ribich, Scott ^{[10
]}

Rekhtman, Natasha ^{[4
]}

Dowlati, Afshin ^{[11
,12
]}

Massion, Pierre P. ^{[13
]}

Rudin, Charles M. ^{[2
,14
,15
]}

Poirier, John T. ^{[2
,15
]}

机构：

[1] Johns Hopkins Univ, Dept Pharmacol & Mol Sci, Pharmacol Grad Training Program, Baltimore, MD USA

[2] Mem Sloan Kettering Canc Ctr, Mol Pharmacol Program, 1275 York Ave, New York, NY 10021 USA

[3] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, 1275 York Ave, New York, NY 10021 USA

[4] Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10021 USA

[5] Mem Sloan Kettering Canc Ctr, Louis V Gerstner Jr Grad Sch Biomed Sci, 1275 York Ave, New York, NY 10021 USA

[6] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA

[7] Mem Sloan Kettering Canc Ctr, Antitumor Assessment Core Facil, 1275 York Ave, New York, NY 10021 USA

[8] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA

[9] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[10] Epizyme Inc, 400 Technol Sq, Cambridge, MA USA

[11] Case Western Reserve Univ, Cleveland, OH 44106 USA

[12] Univ Hosp Case Med Ctr, Cleveland, OH 44106 USA

[13] Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Med Ctr, Nashville, TN USA

[14] Weill Cornell Med Coll, New York, NY 10065 USA

[15] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA

来源：

CANCER CELL | 2017年 / 31卷 / 02期

关键词：

TO-MESENCHYMAL TRANSITION; MUTATIONAL PROCESSES; DNA METHYLATION; TUMOR; SLFN11; METASTASIS; GENE; INHIBITION; EXPRESSION; LINES;

D O I：

10.1016/j.ccell.2017.01.006

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Small cell lung cancer is initially highly responsive to cisplatin and etoposide but in almost every case becomes rapidly chemoresistant, leading to death within 1 year. We modeled acquired chemoresistance in vivo using a series of patient-derived xenografts to generate paired chemosensitive and chemoresistant cancers. Multiple chemoresistant models demonstrated suppression of SLFN11, a factor implicated in DNA-damage repair deficiency. In vivo silencing of SLFN11 was associated with marked deposition of H3K27me3, a histone modification placed by EZH2, within the gene body of SLFN11, inducing local chromatin condensation and gene silencing. Inclusion of an EZH2 inhibitor with standard cytotoxic therapies prevented emergence of acquired resistance and augmented chemotherapeutic efficacy in both chemosensitive and chemoresistant models of small cell lung cancer.

引用

页码：286 / 299

页数：14

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