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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 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 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 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 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 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