Chromosomal instability determines taxane response

C. Swanton, B. Nicke, M. Schuett, Aron Charles Eklund, C. Ng, Q.Y. Li, T. Hardcastle, A. Lee, R. Roy, P. East, M. Kschischo, D. Endesfelder, P. Wylie, S. N. Kim, J. G. Chen, M. Howell, T. Ried, J.K. Habermann, G. Auer, J. D. BrentonZoltan Imre Szallasi, J. Downward

    Research output: Contribution to journalJournal articleResearchpeer-review

    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.
    Original languageEnglish
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume106
    Issue number21
    Pages (from-to)8671-8676
    ISSN0027-8424
    DOIs
    Publication statusPublished - 2009

    Keywords

    • drug resistance
    • chemotherapy

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