Chromosomal instability determines taxane response
Standard
Chromosomal instability determines taxane response. / Swanton, Charles; Nicke, Barbara; Schuett, Marion; Eklund, Aron C; Ng, Charlotte; Li, Qiyuan; Hardcastle, Thomas; Lee, Alvin; Roy, Rajat; East, Philip; Kschischo, Maik; Endesfelder, David; Wylie, Paul; Kim, Se Nyun; Chen, Jie-Guang; Howell, Michael; Ried, Thomas; Habermann, Jens K; Auer, Gert; Brenton, James D; Szallasi, Zoltan; Downward, Julian.
in: P NATL ACAD SCI USA, Jahrgang 106, Nr. 21, 26.05.2009, S. 8671-6.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Chromosomal instability determines taxane response
AU - Swanton, Charles
AU - Nicke, Barbara
AU - Schuett, Marion
AU - Eklund, Aron C
AU - Ng, Charlotte
AU - Li, Qiyuan
AU - Hardcastle, Thomas
AU - Lee, Alvin
AU - Roy, Rajat
AU - East, Philip
AU - Kschischo, Maik
AU - Endesfelder, David
AU - Wylie, Paul
AU - Kim, Se Nyun
AU - Chen, Jie-Guang
AU - Howell, Michael
AU - Ried, Thomas
AU - Habermann, Jens K
AU - Auer, Gert
AU - Brenton, James D
AU - Szallasi, Zoltan
AU - Downward, Julian
PY - 2009/5/26
Y1 - 2009/5/26
N2 - 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.
AB - 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.
KW - Bridged-Ring Compounds/pharmacology
KW - Cell Survival/drug effects
KW - Chromosomal Instability/drug effects
KW - Drug Resistance, Neoplasm/drug effects
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Microtubules/metabolism
KW - Neoplasms/genetics
KW - Paclitaxel/toxicity
KW - Polymerase Chain Reaction
KW - Prognosis
KW - Taxoids/pharmacology
U2 - 10.1073/pnas.0811835106
DO - 10.1073/pnas.0811835106
M3 - SCORING: Journal article
C2 - 19458043
VL - 106
SP - 8671
EP - 8676
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 21
ER -