Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

Abstract

Original ArticlePurpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma

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“…4). This study and others [10][11][12] chemotherapy drugs used to kill cancer cells [13], it is worth noting that large-sample studies have shown extreme heterogeneity among OS patients. Many reports have indicated that the PDX model has strong predictive value for anti-drug resistance in drug response studies [23].…”

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers

“…AZD6738, an ATR inhibitor, has shown preclinical activity in panels of BTC cell lines, particularly with SNU478 and SNU869 cell lines (both p53 MUT ) [ 88 ]. The combination of AZD6738 and MK1775 has also been reported to have synergistic effects in p53 MUT BTC cell lines [ 89 ]. Early phase studies of AZD6738 are ongoing in various cancers [ 90 ] and also AZD6738 in combination with durvalumab in BTCs (NCT04298008).…”

Differential Effects of Combined ATR/WEE1 Inhibition in Cancer Cells

“…Furthermore, a few recent studies have also reported synergistic effects upon combining ATR and WEE1 inhibitors [19][20][21][22]. More specifically, WEE1 and ATR inhibitors caused the synergistic killing of acute myeloid leukemia (AML), biliary tract, and breast cancer cells, likely due to problems arising in S-phase and G2/M [19][20][21]23]. Notably, this combination appears to be well tolerated in mouse models, as it showed little toxicity in normal tissue [19].…”