Dual inhibition of ATR and PARP reverses acquired PARP inhibitor resistance in triple negative breast cancer

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have attracted significant attention in triple negative breast cancer (TNBC) treatment. However, the acquired or de novo PARP inhibitor resistance limits treatment success. Ataxia telangiectasia and Rad3-related (ATR) regulates genome integrity, and thus, the aberrant activation of ATR could play a significant role in the pathogenesis of TNBC and be associated with PARPi resistance in especially homologous recombinant deficiency tumors. We aimed to assess the efficacy of ATR and PARP inhibitors combination in TNBC cells and the reversal of PARPi resistance in resistant cells. HCC1937 and HCC1937-R Talazoparib (TAL) resistant cells were treated with Elimusertib (ELI) alone as ATR inhibitor (ATRi) and ELI and TAL combination. Then, the cytotoxic, apoptotic and ATR based DNA damage response (DDR) were evaluated by WST-1, Annexin V, AO/PI, cell cycle and western blot analysis. Our results showed that the ELI and TAL combination could overcome TAL resistance by downregulating cell cycle checkpoint proteins and ATR-based DDR pathways through synergistic effects (ZIP score > 10). The overexpression of ATR and associated cell cycle proteins could play a role in PARPi resistance. However, this combination did not exert synergism in TNBC cells despite a higher apoptotic rate and increased DNA damage compared with the drug alone. Therefore, the dual targeting of ATR and PARP is a promising modality to reverse PARPi resistance with the downregulation of ATR-Chk1 based DNA damage response. However, further preclinical and clinical investigations should be required to elucidate the underlying molecular mechanisms behind ATRi and PARPi interactions in TNBC cells.