title: 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.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Janzen
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tiourin
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Salehi
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: D Y
authors.initials: DY
authors.lastname: Paik
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, California 90095, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, California 90095, USA.|The VA Greater Los Angeles Health Care System, Los Angeles, California 90073, USA.
authors.forename: S
authors.initials: S
authors.lastname: Memarzadeh
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D018394:CA-125 Antigen / Q000378:metabolism; D016190:Carboplatin / Q000494:pharmacology*; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009368:Neoplasm Transplantation; D018297:Neoplasms, Cystic, Mucinous, and Serous / Q000188:drug therapy / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D059767:Recombinational DNA Repair / Q000235:genetics; D015854:Up-Regulation
chemical_list: D018394:CA-125 Antigen; D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; C451759:MUC16 protein, human; D008565:Membrane Proteins; C582429:birinapant; D016190:Carboplatin; C505530:CASP8 protein, human; D053181:Caspase 8