Reciprocal positive selection for weakness - preventing olaparib resistance by inhibiting BRCA2.

Mateusz Rytelewski,Gabriel Lopez-Berestein,Rene Figueredo,Christian Rodriguez-Aguayo,Larissa Romanow,Anil K Sood,Dahai Jiang,Mark Vincent,Lingegowda S Mangala,Saman Maleki Vareki,James D Koropatnick,Sunila Pradeep,Peter J Ferguson

doi:10.18632/oncotarget.7883

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.

Highlights

Tumor heterogeneity is a feature of most human cancers and increases the probability that small numbers of resistant cells pre-exist at the start of therapy
BRCA2 antisense oligonucleotides (ASOs) treatment sensitized all three lung cancer cell lines to olaparib across the entire range of drug concentrations regardless of mutational signature and load, suggesting that BRCA2 inhibition may render lung tumors with disparate backgrounds sensitive to PARP inhibition
The PARP1 inhibitor olaparib is approved for treatment of BRCA-mutated ovarian tumors

Summary

Introduction

Tumor heterogeneity is a feature of most human cancers and increases the probability that small numbers of resistant cells pre-exist at the start of therapy. Anti-cancer therapy imposes powerful selection pressure on the polyclonal and diverse tumor ecosystem It promotes survival of cells with highest fitness and destroys less fit, more susceptible cells, leading to eventual therapeutic failure: a phenomenon consistent with classical Darwinian evolutionary theory [4]. It is necessary, to design treatment regimens capable www.impactjournals.com/oncotarget of avoiding Darwinian positive selection. Such treatments would not select for fitness and treatment resistance in a heterogeneous tumor cell population, but would select for reduced fitness and susceptibility to treatment

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Conclusion