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.
Highlights
Ovarian cancer (OC) is the deadliest gynecologic malignancy and the American Cancer Society estimates that there will be 22,530 new diagnosis and 13,980 deaths in 2019 [1]
BRCA1/2 are multi-functioning tumor suppressor proteins that play a vital role in homologous recombination repair (HRR) of double-stranded DNA breaks (DSBs), cell cycle checkpoint activation, replication fork (RF) protection, and generating single-stranded DNA during repair after irradiation damage [3,4,5]
This concept led to the discovery that germline BRCA1- and BRCA2-mutated OCs are hypersensitive to poly(ADP-ribose) polymerase (PARP) enzyme inhibition—an enzyme that has an important role in DNA base excision repair [6,7]
Summary
Ovarian cancer (OC) is the deadliest gynecologic malignancy and the American Cancer Society estimates that there will be 22,530 new diagnosis and 13,980 deaths in 2019 [1]. Defective HRR predisposes cancer cells to increased genomic instability and represents a unique vulnerability that can be exploited by anticancer therapy directed at complementary pathways. This concept led to the discovery that germline BRCA1- and BRCA2-mutated OCs are hypersensitive to poly(ADP-ribose) polymerase (PARP) enzyme inhibition—an enzyme that has an important role in DNA base excision repair [6,7]. Based on clinical trial success for patients with recurrent epithelial OC containing a germline BRCA1 or BRCA2 mutation, olaparib was approved in 2014 as a first-in-class PARP inhibitor (PARPi) for treatment of recurrent platinum sensitive OC with a demonstrated progression free survival benefit of 11.2 versus 4.3 months for maintenance therapy compared to placebo [9]. It is thought that tumor cells can develop clinical acquired PARPi resistance over time by two general mechanisms that includes either (a) returned functionality to the HRR pathway by perhaps a somatic restoration of the BRCA1 mutation or evolution of an alternate BRCA1/2-independent HRR pathway or (b) mutations in PARP resulting in reduced
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