Chromosomal instability determines taxane response

被引：215

作者：

Swanton, Charles ^{[2
,3
]}

Nicke, Barbara ^{[2
]}

Schuett, Marion ^{[2
,4
]}

Eklund, Aron C. ^{[5
]}

Ng, Charlotte ^{[1
,6
]}

Li, Qiyuan ^{[5
]}

Hardcastle, Thomas ^{[1
,6
]}

Lee, Alvin ^{[2
]}

Roy, Rajat ^{[2
]}

East, Philip ^{[2
]}

Kschischo, Maik ^{[4
]}

Endesfelder, David ^{[4
]}

Wylie, Paul

Kim, Se Nyun ^{[7
]}

Chen, Jie-Guang

Howell, Michael ^{[2
]}

Ried, Thomas ^{[8
]}

Habermann, Jens K. ^{[9
]}

Auer, Gert ^{[10
]}

Brenton, James D. ^{[1
,10
]}

Szallasi, Zoltan ^{[5
,11
]}

Downward, Julian ^{[2
]}

机构：

[1] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England

[2] Canc Res UK, London Res Inst, London WC2A 3PX, England

[3] Royal Marsden Hosp, Dept Med, Sutton SM2 5PT, Surrey, England

[4] Univ Appl Sci Koblenz, D-53424 Remagen, Germany

[5] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark

[6] Univ Cambridge, Dept Oncol, Cambridge CB2 0XZ, England

[7] Digital Genom Inc, Seoul 120749, South Korea

[8] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA

[9] Univ Hosp Schleswig Holstein, Dept Surg, D-23538 Lubeck, Germany

[10] Karolinska Inst, S-17176 Stockholm, Sweden

[11] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Childrens Hosp Informat Program, Boston, MA 02115 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2009年 / 106卷 / 21期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

chemotherapy; drug resistance; GENE-EXPRESSION; CANCER-CELLS; MULTIDRUG-RESISTANCE; MITOTIC ARREST; CHECKPOINT; PACLITAXEL; DRUG; IDENTIFICATION; REASSORTMENTS; CHEMOTHERAPY;

D O I：

10.1073/pnas.0811835106

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these "CIN-survival'' genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.

引用

页码：8671 / 8676

页数：6

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