Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2
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Mateusz Rytelewski1,6, Saman Maleki Vareki6, Lingegowda S. Mangala3,5, Larissa Romanow1, Dahai Jiang3,4, Sunila Pradeep4, Christian Rodriguez-Aguayo3,4, Gabriel Lopez-Berestein4,5, Rene Figueredo2, Peter J. Ferguson6, Mark Vincent2,6, Anil K. Sood3,5,7, James D. Koropatnick1,2,6
1Department of Microbiology and Immunology, Western University, London, ON, Canada
2Department of Oncology, Western University, London, ON, Canada
3Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Center for RNA Interference and Non-coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Lawson Health Research Institute, London, ON, Canada
7Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
James D. Koropatnick, e-mail: [email protected]
Keywords: DNA repair, resistance, BRCA2, PARP1, antisense
Received: February 09, 2016 Accepted: February 17, 2016 Published: March 03, 2016
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.
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