MUS81 Inhibition Enhances the Anticancer Efficacy of Talazoparib by Impairing ATR/CHK1 Signaling Pathway in Gastric Cancer

Abstract

MUS81 is a critical endonuclease involved in heterodimer formation with Eme1/Mms4 and an important DNA damage repair regulatory molecule. Our previous study suggested that MUS81 was overexpressed and its high expression was positively correlated with gastric cancer metastasis. However, the therapeutic potential of targeting MUS81 in gastric cancer requires further exploration. Therefore, in this study, the Cancer Genome Atlas (TCGA) data were analyzed and showed that MUS81 is a key regulator of cell cycle distribution and DNA damage repair in gastric cancer. In vitro and in vivo, MUS81 knockdown significantly enhanced the anticancer effect of the PARP inhibitor talazoparib. Mechanistically, MUS81 inhibition impaired the activation of the ATR/CHK1 cell cycle signaling pathway and promoted gastric cancer cells with talazoparib-induced DNA damage to continue mitosis. Moreover, addition of the bromodomain-containing protein 4 inhibitor AZD5153 increased the anticancer effect of talazoparib via MUS81 inhibition in gastric cancer cells, and this combination effect was largely impaired when MUS81 was knocked down. In conclusion, these data suggested that MUS81 regulated ATR/CHK1 activation, a key signaling pathway in the G2M checkpoint, and targeting MUS81 enhanced the antitumor efficacy of talazoparib. Therefore, AZD5153 combined with talazoparib may represent a promising therapeutic strategy for patients with MUS81 proficient gastric cancer.

Combination of PARP inhibitor and CDK4/6 inhibitor modulates cGAS/STING‐dependent therapy‐induced senescence and provides “one‐two punch” opportunity with anti‐PD‐L1 therapy in colorectal cancer

“…The colorectal cancer cell lines were seeded in 96‐well plates at 1 × 10 3 cells/well and cultured overnight in the medium before adding DMSO, talazoparib, palbociclib, or talazoparib combined with palbociclib for treatment. Five days after drug treatment, cell proliferation was measured using the CellTiter™ AQueous assay (MTS; Promega) 11 . Each group contained five technical replicates of three independent experiments.…”

“…After treatment with the corresponding drugs, flow cytometry was performed to detect apoptosis and cell cycle progression, as previously reported 11 . Cell apoptosis and cell cycle detection were repeated three times.…”

“…Currently, new combination regimens and strategies have been applied to selectively enhance the efficacy of PARPi in multiple preclinical cancer models, 1,9–11 such as chemotherapy agents, radiotherapy, immunotherapy, and small molecule inhibitors, but we still need further evidence to promote these strategies into clinical application 12 . Besides, although targeting cell cycle checkpoint kinases including ATR/CHK1 and ATM/CHK2 was theoretically feasible to elevate the anticancer effect of PARPi via impairing HR repair capacity, the safety and efficacy of these targeted drugs need to be proved by further clinical trials 11,13 . Thus, exploring an FDA‐approved drug to sensitize the efficacy of PARPi may expand the population of the cancer patients who benefit from PARPi treatment.…”

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

“…There, MUS81 promotes single-stranded DNA formation in dependency on R-loops, which in turn activates ATR [ 77 ]. Indeed, inhibition of MUS81 in gastric cancer cells induces cell death in an ATR-Chk1-dependent mechanism [ 78 ], which could be due to excessive R-loop mediated DNA damage.…”

Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy

“…Several nucleases that process stressed replication forks are being explored as therapeutic targets. MUS81 cleaves stalled replication forks to initiate HR-mediated fork restart [ 100 ], and it has shown promise as a target in preclinical studies [ 131 , 174 ]. EEPD1 also cleaves stalled replication forks [ 103 , 104 ] and given that MUS81 and EEPD1 cleave forks with different polarity, combining MUS81i and EEPD1i may be potent approach to augment the cytotoxic effects of replication stress.…”