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.

• Authors: D M Janzen, E Tiourin, J A Salehi, D Y Paik, J Lu, M Pellegrini, S Memarzadeh
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 7956 (Aug 03 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26234182 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• CA-125 Antigen
• Dipeptides
• Indoles
• Inhibitor of Apoptosis Proteins
• MUC16 protein, human
• Membrane Proteins
• birinapant
• Carboplatin
• CASP8 protein, human
• Caspase 8

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects, genetics)
• CA-125 Antigen (metabolism)
• Carboplatin (pharmacology)
• Caspase 8 (drug effects, metabolism)
• Dipeptides (pharmacology)
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Indoles (pharmacology)
• Inhibitor of Apoptosis Proteins (drug effects, metabolism)
• Membrane Proteins (metabolism)
• Mice
• Neoplasm Transplantation
• Neoplasms, Cystic, Mucinous, and Serous (drug therapy, genetics)
• Ovarian Neoplasms (drug therapy, genetics)
• Recombinational DNA Repair (genetics)
• Up-Regulation