RETRACTED ARTICLE: An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer

D. M. Janzen, E. Tiourin, J. A. Salehi, D. Y. Paik, J. Lu, M. Pellegrini and S. Memarzadeh ()
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D. M. Janzen: David Geffen School of Medicine, University of California, Los Angeles
E. Tiourin: David Geffen School of Medicine, University of California, Los Angeles
J. A. Salehi: David Geffen School of Medicine, University of California, Los Angeles
D. Y. Paik: David Geffen School of Medicine, University of California, Los Angeles
J. Lu: Cell and Developmental Biology, University of California, Los Angeles
M. Pellegrini: Cell and Developmental Biology, University of California, Los Angeles
S. Memarzadeh: David Geffen School of Medicine, University of California, Los Angeles

Nature Communications, 2015, vol. 6, issue 1, 1-18

Abstract: Abstract High-grade serous ovarian cancers (HGSCs) are deadly malignancies that relapse despite carboplatin chemotherapy. Here we show that 16 independent primary HGSC samples contain a CA125-negative population enriched for carboplatin-resistant cancer initiating cells. Transcriptome analysis reveals upregulation of homologous recombination DNA repair and anti-apoptotic signals in this population. While treatment with carboplatin enriches for CA125-negative cells, co-treatment with carboplatin and birinapant eliminates these cells in HGSCs expressing high levels of the inhibitor of apoptosis protein cIAP in the CA125-negative population. Birinapant sensitizes CA125-negative cells to carboplatin by mediating degradation of cIAP causing cleavage of caspase 8 and restoration of apoptosis. This co-therapy significantly improves disease-free survival in vivo compared with either therapy alone in tumour-bearing mice. These findings suggest that therapeutic strategies that target CA125-negative cells may be useful in the treatment of HGSC.

Date: 2015
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DOI: 10.1038/ncomms8956

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