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; S Memarzadeh

doi:10.1038/ncomms8956

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.

Authors

D M Janzen¹, E Tiourin¹, J A Salehi¹, D Y Paik¹, J Lu², M Pellegrini^{2

3}, S Memarzadeh^{1

3

4}

Affiliations

¹ Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
² Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.
³ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California 90095, USA.
⁴ The VA Greater Los Angeles Health Care System, Los Angeles, California 90073, USA.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding