Anti‐tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells

Kim, Hee Jun; Min, Ahrum; Im, Seock Ah; Jang, Hyemin; Lee, Kyung Hun; Lau, Alan; Lee, Miso; Kim, Seongyeong; Yang, Yaewon; Kim, Jung-Eun; Kim, Tae Yong; Oh, Do Youn; Brown, Jeffrey L.; O’Connor, Mark J.; Bang, Yung Jue

doi:10.1002/ijc.30373

Cited by 52 publications

(36 citation statements)

References 32 publications

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“…The researchers demonstrated that Rad51 inactivation and γ-H2AX accumulation were more significantly observed after combination treatment. Notably, ATR inhibitor as single agents has been evaluated in HER2-positive breast cancer [24]. The investigators found that AZD6738 reduced several DNA repair proteins and p-AKT levels in sensitive cells but not in insensitive cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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“…Of note, recent data indicate that the ATR inhibitor AZD6738 is able to penetrate the blood brain barrier, 36 and that ATR knockdown leads to significant sensitization to temozolomide in a glioma cell line. 37 This approach has also been studied in other cancers: ATR inhibition with AZD6738 combined with other therapies proved to be synergistic for pancreatic cancer (ATRi and Gemcitabine), 38 Her2-positive breast cancer (ATRi and Cisplatin), 39 and non-small cell lung cancer (ATRi and Cisplatin). 40 In radiotherapy of glioblastoma, replication stress leading to constitutive activation of the DNA damage response pathway under irradiation is thought to mediate radioresistance.…”

Section: Discussionmentioning

confidence: 99%

Experimental glioma with high bHLH expression harbor increased replicative stress and are sensitive toward ATR inhibition

Koch

Czemmel

Lennartz

et al. 2020

Neuro-Oncology Advances

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Background The overexpression of (basic)helix-loop-helix ((b)HLH) transcription factors is frequent in malignant glioma. We investigated molecular effects upon disruption of the (b)HLH network by a dominant negative variant of the E47 protein (dnE47). Our goal was to identify novel molecular subgroup-specific therapeutic strategies. Methods Glioma cell lines LN229, LNZ308 and GS-2/GS-9 were lentivirally transduced. Functional characterization included immunocytochemistry, immunoblots, cytotoxic and clonogenic survival assays in vitro, and latency until neurological symptoms in vivo. Results of cap analysis gene expression (CAGE) and RNA sequencing (RNA-Seq) were further validated by immunoblot, flow cytometry and functional assays in vitro. Results The induction of dnE47-RFP led to cytoplasmic sequestration of (b)HLH transcription factors and anti-glioma activity in vitro and in vivo. Downstream molecular events, i.e. alterations in transcription start site usage and in the transcriptome revealed enrichment of cancer-relevant pathways, particularly of the DNA damage response (DDR) pathway. Pharmacologic validation of this result using ATR inhibition led to a significantly enhanced early and late apoptotic effect compared to temozolomide alone. Conclusions Gliomas overexpressing (b)HLH transcription factors are sensitive towards inhibition of the ATR kinase. The combination of ATR inhibition plus temozolomide or radiation therapy in this molecular subgroup are warranted.

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“…Both NF-κB transcription factors and Src proto-oncogene were previously connected with tumorigenesis [67] and breast cancer metastasis [68]. Distant metastasis developed in lymph node negative luminal A patients was associated with cell cycle, DNA repair and immune response mechanisms [69][70][71]. In lymph node positive luminal A patients, distant metastasis was related to mechanisms of T lymphocyte differentiation and activation [72,73] (Figure 2).…”

Section: Molecular Mechanism Associated With Lymph Node and Distant Mmentioning

confidence: 94%

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

Lapčík

Pospíšilová

Janáčová

et al. 2020

Cancers

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Lymph node status is one of the best prognostic factors in breast cancer, however, its association with distant metastasis is not straightforward. Here we compare molecular mechanisms of nodal and distant metastasis in molecular subtypes of breast cancer, with major focus on luminal A patients. We analyze a new cohort of 706 patients (MMCI_706) as well as an independent cohort of 836 primary tumors with full gene expression information (SUPERTAM_HGU133A). We evaluate the risk of distant metastasis, analyze targetable molecular mechanisms in Gene Set Enrichment Analysis and identify relevant inhibitors. Lymph node positivity is generally associated with NF-κB and Src pathways and is related to high risk (OR: 5.062 and 2.401 in MMCI_706 and SUPERTAM_HGU133A, respectively, p < 0.05) of distant metastasis in luminal A patients. However, a part (≤15%) of lymph node negative tumors at the diagnosis develop the distant metastasis which is related to cell proliferation control and thrombolysis. Distant metastasis of lymph node positive patients is mostly associated with immune response. These pro-metastatic mechanisms further vary in other molecular subtypes. Our data indicate that the management of breast cancer and prevention of distant metastasis requires stratified approach based on targeted strategies.

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Anti‐tumor activity of the ATR inhibitor AZD6738 in HER2 positive breast cancer cells

Cited by 52 publications

References 32 publications

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

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

Experimental glioma with high bHLH expression harbor increased replicative stress and are sensitive toward ATR inhibition

How Different Are the Molecular Mechanisms of Nodal and Distant Metastasis in Luminal A Breast Cancer?

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