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

• Published in: Nature communications 2015-08, Vol.6, p.7956-7956
• Main Authors: Janzen, D M, Tiourin, E, Salehi, J A, Paik, D Y, Lu, J, Pellegrini, M, Memarzadeh, S
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; CA-125 Antigen - metabolism; Cancer; Carboplatin; Carboplatin - pharmacology; Caspase; Caspase 8 - drug effects; Caspase 8 - metabolism; Caspase-8; Chemotherapy; Dipeptides - pharmacology; DNA repair; Drug Resistance, Neoplasm - genetics; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - genetics; Homologous recombination; Homology; Humans; Indoles - pharmacology; Inhibitor of Apoptosis Proteins - drug effects; Inhibitor of Apoptosis Proteins - metabolism; Membrane Proteins - metabolism; Mice; Neoplasm Transplantation; Neoplasms, Cystic, Mucinous, and Serous - drug therapy; Neoplasms, Cystic, Mucinous, and Serous - genetics; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Platinum; Recombinational DNA Repair - genetics; Restoration; Tumors; Up-Regulation
• ISSN: 2041-1723
• DOI: 10.1038/ncomms8956

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.