Chromosomal instability determines taxane response.
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.
Swanton
Charles
C
Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom.
Nicke
Barbara
B
Schuett
Marion
M
Eklund
Aron C
AC
Ng
Charlotte
C
Li
Qiyuan
Q
Hardcastle
Thomas
T
Lee
Alvin
A
Roy
Rajat
R
East
Philip
P
Kschischo
Maik
M
Endesfelder
David
D
Wylie
Paul
P
Kim
Se Nyun
SN
Chen
Jie-Guang
JG
Howell
Michael
M
Ried
Thomas
T
Habermann
Jens K
JK
Auer
Gert
G
Brenton
James D
JD
Szallasi
Zoltan
Z
Downward
Julian
J
D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D043171:Chromosomal Instability / Q000187:drug effects* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000633:toxicity; D016133:Polymerase Chain Reaction; D011379:Prognosis; D043823:Taxoids / Q000494:pharmacology*
D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D017239:Paclitaxel