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


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.

SUBMITTER: Janzen DM 

PROVIDER: S-EPMC4532886 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Janzen D M DM   Tiourin E E   Salehi J A JA   Paik D Y DY   Lu J J   Pellegrini M M   Memarzadeh S S  

Nature communications 20150803


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 birin  ...[more]

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