title: Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2.
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.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, ON, Canada.|Lawson Health Research Institute, London, ON, Canada.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Rytelewski
authors.affiliation: Lawson Health Research Institute, London, ON, Canada.
authors.forename: Saman
authors.initials: S
authors.lastname: Maleki Vareki
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: Department of Microbiology and Immunology, Western University, London, ON, Canada.
authors.forename: Larissa
authors.initials: L
authors.lastname: Romanow
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Dahai
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Department of Oncology, Western University, London, ON, Canada.
authors.forename: Rene
authors.initials: R
authors.lastname: Figueredo
authors.affiliation: Lawson Health Research Institute, London, ON, Canada.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ferguson
authors.affiliation: Department of Oncology, Western University, London, ON, Canada.|Lawson Health Research Institute, London, ON, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Vincent
authors.affiliation: Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Microbiology and Immunology, Western University, London, ON, Canada.|Department of Oncology, Western University, London, ON, Canada.|Lawson Health Research Institute, London, ON, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Koropatnick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D059767:Recombinational DNA Repair / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D010793:Phthalazines; D010879:Piperazines; D034741:RNA, Small Interfering; C531550:olaparib
keywords: BRCA2; DNA repair; PARP1; antisense; resistance