Olaparib Combined with an ATR or Chk1 Inhibitor as a Treatment Strategy for Acquired Olaparib-Resistant BRCA1 Mutant Ovarian Cells

Abstract

Objective: Despite the promise of PARP inhibitors (PARPi) for treating BRCA1/2 mutated ovarian cancer (OC), drug resistance invariably develops. We hypothesized rationale drug combinations, targeting key molecules in DNA repair pathways and the cell cycle may be synergistic and overcome acquired PARPi resistance. Methods: Drug sensitivity to PARPi alone and in combination with inhibitors of key DNA repair and cell cycle proteins, including ATR (VE-821), Chk1 (MK-8776), Wee1 (MK-1775), RAD51 (RI-1) was assessed in PARPi-sensitive (UWB1) and -resistant (UWB1-R) gBRCA1 mutant OC cell lines using a cell proliferation assay. The Bliss synergy model was used to estimate the two-drug combination effect and pharmacologic synergy (Bliss score ≥ 0) or antagonistic (Bliss score ≥ 0) response of the PARPi in combination with the inhibitors. Results: IC50 for olaparib alone was 1.6 ± 0.9 µM compared to 3.4 ± 0.6 µM (p = 0.05) for UWB1 and UWB1-R cells, respectively. UWB1-R demonstrated increased sensitivity to ATRi (p = 0.04) compared to UWB1. Olaparib (0.3–1.25 µM) and ATRi (0.8–2.5 µM) were synergistic with Bliss scores of 17.2 ± 0.2, 11.9 ± 0.6 for UWB1 and UWB1-R cells, respectively. Olaparib (0.3–1.25 µM) and Chk1i(0.05–1.25 µM) were synergistic with Bliss scores of 8.3 ± 1.6, 5.7 ± 2.9 for UWB1 and UWB1-R cells, respectively. Conclusions: Combining an ATRi or Chk1i with olaparib is synergistic in both PARPi-sensitive and -resistant BRCA1 mutated OC cell models, and are rationale combinations for further clinical development.

Modulation of Early Mitotic Inhibitor 1 (EMI1) Depletion on the Sensitivity of PARP Inhibitors in BRCA1 Mutated Triple-Negative Breast Cancer Cells

“…Results presented in this study confirm this notion for BRCA1-mutant breast cancer cells. These results are consistent with recently published results for other BRCA1/2 mutant olaparib sensitive and olaparib resistant ovarian cancer cell lines (37). These results suggest a potential treatment strategy toward overcoming PARPi resistance in BRCA1 associated breast cancer cells.…”

The Rna-binding Protein GRSF1 Promote shepatocarcinogenesis via competitively Binding Toyy1 mRNA with mIR-30e-5p

“…Dias et al reported VE-821 could induced cancer cells death [39] . Another report also uncovered VE-821 induced BRCA1 Mutant Ovarian Cells death [40] . The data in this study uncovered that VE-821 prevented HCC progression by repressing GRSF1/YY1 axis and enhanced miR-30e-5p expression.…”

“…However, whether VE-821 could be used as a novel clinical treatment option for HCC patients deservedly requires deeper researches. In addition, recent research suggested that VE-821 showed a synergistic effect with PD-L1 inhibition in pancreatic cancer, and PD-L1 inhibition increased VE-821 sensitivity [40] . GRSF1 is necessary in the progression of ATR-dependent regulation on Dux, which is vital for the cleavage-speci c transcription [41] .Therefore, whether the combination with PD-L1 inhibition could improve antitumor function of VE-821 on HCC induced by GRSF1 is worth to be further discussed in the future.…”

“…After treated with or without VE821 for 48 h, MHCC-97H cells in different dish were added with cycloheximide (CHX, 50 g/ml) at the same time. At indicted time points (0, 5,10,15,20,25,30,35,40 and 45 h), protein samples were collected and then analyzed by western blotting assay.…”

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

“…In BRCA1-deficient cells, ATR inhibitors (ATRi) disrupted the acquired ATR-dependent recruitment of PALB2-BRCA2 and RAD51 loading [135,136], thereby reestablishing HR deficiency and overcoming the RAD51-related protection of stalled forks. The synergistic anti-tumor effect of combination PARPi and ATRi was demonstrated in PARPi-resistant BRCA1-mutant EOC models [137] and breast cancer models [138]. Furthermore, the role of ATR in coupling DNA damage repair with cell cycle regulation enhances the synergism of combination ATRi and PARPi, particularly in p53-mutated EOC [139].…”