Reference Detail

Ref Type

Journal Article

PMID

(32220892)

Authors

Yang L, Shen C, Pettit CJ, Li T, Hu AJ, Miller ED, Zhang J, Lin SH, Williams TM

Title

Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2020 Mar 27	3740-3750	Clin Cancer Res

URL

Abstract Text

Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G2-M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G2-M checkpoint sensitizes esophageal cancer cells to radiotherapy.Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 in vivo.The IC50 concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G2-M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts.Abrogation of G2-M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	gastric adenocarcinoma	no benefit	Adavosertib + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, Adavosertib (MK-1775) treatment did not sensitize TP53 wild-type gastric adenocarcinoma cells to radiation therapy in culture (PMID: 32220892).	32220892
TP53 mutant	esophagus squamous cell carcinoma	predicted - sensitive	Adavosertib	Preclinical - Cell culture	Actionable	In a preclinical study, Adavosertib (MK-1775) treatment inhibited viability of TP53-mutant esophageal squamous cell carcinoma cells in culture (PMID: 32220892).	32220892
TP53 mutant	esophagus adenocarcinoma	predicted - sensitive	Adavosertib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Adavosertib (MK-1775) treatment inhibited phosphorylation of Wee1 and Cdk1, and reduced viability of TP53-mutant esophageal adenocarcinoma cells in culture, and led to partial tumor growth delay in cell line xenograft models (PMID: 32220892).	32220892
TP53 mutant	esophagus squamous cell carcinoma	sensitive	Adavosertib + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, Adavosertib (MK-1775) treatment enhanced sensitivity of TP53-mutant esophageal squamous cell carcinoma cells to radiation therapy, resulting in decreased colony formation in culture (PMID: 32220892).	32220892
TP53 mutant	esophagus adenocarcinoma	sensitive	Adavosertib + Radiotherapy	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Adavosertib (MK-1775) treatment enhanced sensitivity of TP53-mutant esophageal adenocarcinoma cells to radiation therapy, resulting in inhibition of phosphorylation of Wee1 and Cdk1, reduced colony formation, and increased DNA damage and mitotic cell death in culture, and tumor growth inhibition and regression in cell line xenograft models (PMID: 32220892).	32220892