title: Chromosomal instability determines taxane response.
abstract: 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.
authors.affiliation: Cancer Research UK, London Research Institute, London WC2A 3PX, United Kingdom.
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.forename: Barbara
authors.initials: B
authors.lastname: Nicke
authors.forename: Marion
authors.initials: M
authors.lastname: Schuett
authors.forename: Aron C
authors.initials: AC
authors.lastname: Eklund
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ng
authors.forename: Qiyuan
authors.initials: Q
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Hardcastle
authors.forename: Alvin
authors.initials: A
authors.lastname: Lee
authors.forename: Rajat
authors.initials: R
authors.lastname: Roy
authors.forename: Philip
authors.initials: P
authors.lastname: East
authors.forename: Maik
authors.initials: M
authors.lastname: Kschischo
authors.forename: David
authors.initials: D
authors.lastname: Endesfelder
authors.forename: Paul
authors.initials: P
authors.lastname: Wylie
authors.forename: Se Nyun
authors.initials: SN
authors.lastname: Kim
authors.forename: Jie-Guang
authors.initials: JG
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Howell
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Jens K
authors.initials: JK
authors.lastname: Habermann
authors.forename: Gert
authors.initials: G
authors.lastname: Auer
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: 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*
chemical_list: D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane; D017239:Paclitaxel