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Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2. Oncotarget 2016 Apr 12;7(15):20825-39

Date

03/10/2016

Pubmed ID

26959114

Pubmed Central ID

PMC4991495

DOI

10.18632/oncotarget.7883

Scopus ID

2-s2.0-84964755416   6 Citations

Abstract

Human tumor heterogeneity promotes therapeutic failure by increasing the likelihood of resistant cell subpopulations. The PARP-1 inhibitor olaparib is approved for use in BRCA-mutated ovarian cancers but BRCA2-reversion mutations lead to functional homologous recombination repair (HRR) and olaparib resistance. To overcome that resistance and expand use of PARP1 inhibition to cancers with functional HRR, we developed an antisense strategy to render the majority of tumor cells in a population BRCA2-deficient. We predicted that this strategy would render HRR-proficient tumor cells sensitive to olaparib and prevent emergence of resistance in a tumor cell population heterogeneous for HRR proficiency. We report that BRCA2 downregulation sensitized multiple human tumor cell lines (but not non-cancer human kidney cells) to olaparib and, combined with olaparib, increased aneuploidy and chromosomal translocations in human tumor cells. In a mixed HRR-proficient and HRR-deficient cell population, olaparib monotherapy allowed outgrowth of HRR-proficient cells resistant to subsequent olaparib treatment. Combined BRCA2 inhibition and olaparib treatment prevented selection of HRR-proficient cells and inhibited proliferation of the entire population. Treatment with BRCA2 siRNA and olaparib decreased ovarian xenograft growth in mice more effectively than either treatment alone. In vivo use of BRCA2 antisense oligonucleotides may be a viable option to expand clinical use of olaparib and prevent resistance.

Author List

Rytelewski M, Maleki Vareki S, Mangala LS, Romanow L, Jiang D, Pradeep S, Rodriguez-Aguayo C, Lopez-Berestein G, Figueredo R, Ferguson PJ, Vincent M, Sood AK, Koropatnick JD

Author

Sunila Pradeep PhD Assistant Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Antineoplastic Agents
Apoptosis
BRCA2 Protein
Biomarkers, Tumor
Cell Proliferation
Drug Resistance, Neoplasm
Female
Humans
Mice
Mice, Nude
Ovarian Neoplasms
Phthalazines
Piperazines
RNA, Small Interfering
Recombinational DNA Repair
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a