Finally, we found that mTOR inhibitors suppress SUV39H1, a novel mechanism by which they regulate HR repair and synergize with PARP inhibitors. In addition, combination treatment of BRCA-proficient TNBCs with mTOR inhibitors and PARP inhibitors synergistically inhibits proliferation in vitro and exhibits enhanced efficacy in vivo. Here, we report that mTOR inhibitors are highly effective in suppressing HR repair. To expand the spectrum of TNBC patients who would benefit from PARP inhibitors, especially those that are BRCA-proficient, rational combination therapies that lead to homologous recombination (HR) defects and consequently synergize with PARP inhibitors should be evaluated. PARP inhibitors provide benefit for TNBC with BRCA1/ BRCA2 mutations. Novel targeted therapies are urgently needed for triple-negative breast cancer (TNBC) that have limited therapeutic options and poor prognosis. We further identified through microarray analysis and by rescue assays that mTOR inhibitors suppressed HR repair and synergized with PARP inhibitors through regulating the expression of SUV39H1 in BRCA-proficient TNBCs.Ĭonclusions: Collectively, these findings strongly suggest that combining mTOR inhibitors and PARP inhibitors would be an effective therapeutic approach to treat BRCA-proficient TNBC patients. In TNBC xenografts, we observed enhanced efficacy of everolimus in combination with talazoparib (BMN673) compared with either drug alone. mTOR inhibitors and PARP inhibitors in combination exhibited strong synergism against these TNBC cell lines. Results: We found that mTOR inhibitors significantly suppressed HR repair in two BRCA-proficient TNBC cell lines. Moreover, microarray analysis and rescue experiments were used to investigate the molecular mechanisms of action. We further demonstrated the in vitro and in vivo activities of combined treatment of mTOR inhibitors with PARP inhibitors in BRCA-proficient TNBC.
Here we explored whether mTOR inhibitors, through modulating homologous recombination (HR) repair, would provide therapeutic benefit in combination with PARP inhibitors in preclinical models of BRCA-proficient TNBC.Įxperimental Design: We have studied the effects of mTOR inhibitors on HR repair following DNA double-strand breaks (DSB). Although PARP inhibitors represent a promising treatment in TNBC with BRCA1/ BRCA2 mutations, there is great interest in identifying drug combinations that can extend the use of PARP inhibitors to a majority of TNBC patients with wild-type BRCA1/ BRCA2.
Purpose: Triple-negative breast cancer (TNBC) is a highly heterogeneous disease and has the worst outcome among all subtypes of breast cancers.
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