Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations.

Abstract

PURPOSE:

The mechanism of action of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentofuranosyl-cytosine) is unique among deoxycytidine analogs because upon incorporation into DNA it causes a single strand break which is converted to a double strand break after DNA replication. This lesion requires homologous recombination (HR) for repair. CNDAC, as the parent nucleoside, DFP10917, and as an oral prodrug, sapacitabine, are undergoing clinical trials for hematological malignancies and solid tumors. The purpose of this study is to investigate the potential of CNDAC for the therapy of ovarian cancer (OC).

METHODS:

Drug sensitivity was evaluated using a clonogenic survival assay. Drug combination effects were quantified by median effect analysis.

RESULTS:

OC cells lacking function of the key HR genes, BRCA1 or BRCA2, were more sensitive to CNDAC than corresponding HR proficient cells. The sensitization was associated with greater levels of DNA damage in response to CNDAC at clinically achievable concentrations, manifested as chromosomal aberrations. Three classes of CNDAC-based drug combinations were investigated. First, the PARP1 inhibitors, rucaparib and talazoparib, were selectively synergistic with CNDAC in BRCA1/2 deficient OC cells (combination index < 1) at a relatively low concentration range. Second, cisplatin and oxaliplatin had additive combination effects with CNDAC (combination index ~ 1). Finally, paclitaxel and docetaxel achieved additive cell-killing effects with CNDAC at concentration ranges of the taxanes similar for both BRCA1/2 deficient and proficient OC cells.

CONCLUSIONS:

This study provides mechanistic rationales for combining CNDAC with PARP inhibitors, platinum compounds and taxanes in ovarian cancer lacking BRCA1/2 function.

• Authors: Xiaojun Liu, Yingjun Jiang, Billie Nowak, Bethany Qiang, Nancy Cheng, Yuling Chen, William Plunkett
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 81 Issue 2 Pg. 255-267 (02 2018) ISSN: 1432-0843 [Electronic] Germany
• PMID: 29189915 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• BRCA1 protein, human
• BRCA2 Protein
• BRCA2 protein, human
• Organoplatinum Compounds
• Cytarabine
• 2'-cyano-2'-deoxyarabinofuranosylcytosine
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Antineoplastic Agents (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• BRCA1 Protein (drug effects, genetics)
• BRCA2 Protein (drug effects, genetics)
• Cell Line, Tumor
• Chromosome Aberrations (drug effects)
• Cytarabine (analogs & derivatives, therapeutic use)
• DNA Damage
• Drug Synergism
• Female
• Humans
• Organoplatinum Compounds (therapeutic use)
• Ovarian Neoplasms (drug therapy, genetics)
• Poly (ADP-Ribose) Polymerase-1
• Tumor Stem Cell Assay