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

Nat Commun. 2015 Aug 3:6:7956. doi: 10.1038/ncomms8956.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • CA-125 Antigen / metabolism
  • Carboplatin / pharmacology*
  • Caspase 8 / drug effects
  • Caspase 8 / 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*
  • 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 Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Recombinational DNA Repair / genetics
  • Up-Regulation

Substances

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