B6
Functional genomic annotation of microtubule stabiliser response defines chromosomal instability as a determinant of taxane sensitivity in vivo
Charles Swanton1, Barbara Nicke1, Marion Schuett1, Aron Eklund4, Charlotte Ng2, Thomas Hardcastle2, Qiyuan Li4, Thomas Ried5, Gert Auer6, Jens Haberman8, Maik Kschischo7, Phil East1, Alvin Lee1, Zoltan Szallasi3, James Brenton2, Julian Downward1
1Cancer Research UK London Research Institute, London, UK, 2Cancer Research UK Cambridge Research Institute, Cambridge, UK, 3Harvard Medical School, Boston, USA, 4Technical University of Denmark, Lyngby, Denmark, 5NCI National Institute of Health, Bethesda, USA, 6Karolinska Institutet, Stockholm, Sweden, 7University of Applied Sciences, Remagen, Germany, 8University Hospital Schleswig-Holstein, Lubeck, Germany
Background
Mechanisms of cancer cell death following taxane treatment remain poorly defined. In a RNA interference screen we identified many genes that induce taxane resistance and aneuploidy independent of drug treatment. This suggested that pathways that prevent chromosomal instability (CIN) are functionally related to taxane response.
Method and results
We derived a gene expression signature induced by microtubule stabilising (MTS) agents from 5 public microarray datasets. Over-expression of genes repressed in the MTS-response signature defined poor survival in 10 independent cancer cohorts. There was significant overlap between genes repressed within the MTS gene signature and a signature of genes over-expressed in tumours with CIN. RNAi silencing of these genes promoted cytotoxicity, thereby identifying “MTS-cytotoxic genes”.
qRT-PCR analysis of MTS-cytotoxic genes following taxane treatment demonstrated robust repression in diploid CINlow cancer cells that initiate mitotic arrest and death in response to paclitaxel. In contrast, CINhigh cancer cell lines fail to repress MTS-cytotoxic genes following taxane treatment, triggering mitotic arrest but not cell death. Importantly, cancers from the CTCR-OV01 trial displaying the CIN signature demonstrate primary resistance to taxane monotherapy but sensitivity to carboplatin, indicating that CIN may predict cytotoxic drug response in vivo. DNA image cytometry on 48 samples correctly identified CIN tumours.
Conclusion
CIN may determine response to taxane therapy in vivo and DNA image cytometry is a sensitive technique to identify CIN tumours from paraffin material. This allows the pre-therapeutic assessment of genomic instability status to stratify patients for platinum or taxane therapies within prospective clinical trials.
