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Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy Linlin Yang1, Changxian Shen1, Cory J

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Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy Linlin Yang1, Changxian Shen1, Cory J Published OnlineFirst March 27, 2020; DOI: 10.1158/1078-0432.CCR-19-3373 CLINICAL CANCER RESEARCH | TRANSLATIONAL CANCER MECHANISMS AND THERAPY Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy Linlin Yang1, Changxian Shen1, Cory J. Pettit1, Tianyun Li1, Andrew J. Hu1, Eric D. Miller1, Junran Zhang1, Steven H. Lin2, and Terence M. Williams1 ABSTRACT ◥ Purpose: Esophageal cancer is a deadly malignancy with a 5-year (100 nmol/L) as monotherapy did not alter the viability of survival rate of only 5% to 20%, which has remained unchanged for esophageal cancer cells, but significantly radiosensitized esoph- decades. Esophageal cancer possesses a high frequency of TP53 ageal cancer cells. AZD1775 significantly abrogated radiation- mutations leading to dysfunctional G1 cell-cycle checkpoint, which induced G2–M phase arrest and attenuation of p-CDK1-Y15. – likely makes esophageal cancer cells highly reliant upon G2 M Moreover, AZD1775 increased radiation-induced mitotic checkpoint for adaptation to DNA replication stress and DNA catastrophe, which was accompanied by increased gH2AX damage after radiation. We aim to explore whether targeting Wee1 levels, and subsequently reduced survival after radiation. – kinase to abolish G2 M checkpoint sensitizes esophageal cancer Importantly, AZD1775 in combination with radiotherapy cells to radiotherapy. resulted in marked tumor regression of esophageal cancer tumor Experimental Design: Cell viability was assessed by cytotoxicity xenografts. – and colony-forming assays, cell-cycle distribution was analyzed by Conclusions: Abrogation of G2 M checkpoint by targeting flow cytometry, and mitotic catastrophe was assessed by immuno- Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to fluorescence staining. Human esophageal cancer xenografts were radiotherapy in vitro and in mouse xenografts. Our findings generated to explore the radiosensitizing effect of AZD1775 in vivo. suggest that inhibition of Wee1 by AZD1775 is an effective Results: The IC50 concentrations of AZD1775 on esophageal strategy for radiosensitization in esophageal cancer and warrants cancer cell lines were between 300 and 600 nmol/L. AZD1775 clinical testing. Introduction response to ever-changing intracellular and extracellular genotoxic insults, cells activate DNA damage, replication, and mitotic check- Esophageal cancer is the sixth leading cause of cancer-related death points, which function to inhibit the activity of CDKs and halt cell- and affects more than 450,000 people worldwide (1). Standard-of-care cycle progression to provide time to repair DNA damage and fix therapy for localized esophageal cancer is radiotherapy and chemo- chromatin disruption (7). The fine coupling of cell cycle and DNA therapy followed by surgery, but recurrence rates remain high. More- damage checkpoints ensures genome integrity and cell survival (7). over, approximately of 50% patients diagnosed with esophageal cancer Aberrant activation of CDKs and hence uncontrolled cell-cycle pro- present with unresectable or metastatic disease (2). In the past decade, gression is a hallmark of cancer cells (8). Many human cancers have although great advances have been made for the prevention and deficits in G –S checkpoint due to mutations in the p53 signaling axis control of many cancers such as lung cancer and breast cancer, the 1 including mutations of TP53, CDKN2A, and RB (9). Treatment of overall 5-year survival rate of patients with esophageal cancer remains these cells with radiation induces a G –M arrest, allowing time for below 20% and the incidence is increasing rapidly worldwide (1, 3, 4). 2 DNA repair, thus leading to a higher level of dependence of these Therefore, there is an urgent need to develop novel effective therapies cancer cells on G –M checkpoint for survival. In these cases, genetic for the management of esophageal cancer (2, 5). 2 abrogation of the G –M checkpoint may allow entry of cells into Proper cell proliferation and accurate genetic material duplication 2 mitosis with incompletely-repaired damaged DNA, ultimately leading depends on the tight and fine coordination of the cell-cycle surveillance to mitotic catastrophe and cell death (10). It has therefore been systems including G –G ,S,G, and M cell-cycle checkpoints (6). 0 1 2 proposed that small molecules targeting G –M checkpoint are prom- Cell-cycle progression is controlled by cyclin-dependent kinases 2 ising cancer therapy agents either as monotherapy or in combination (CDK), which are regulated by cell growth and mitogenic signals. In with radiotherapy and chemotherapy (5, 11–13). Wee1 kinase is essential for scheduled cell division through inhib- itory phosphorylation of CDK1 and CDK2 at the conserved tyrosine15 1The Ohio State University Medical Center, Arthur G. James Comprehensive 2 residue (14). Particularly, Wee1-mediated phosphorylation and inhi- Cancer Center and Richard J. Solove Research Institute, Columbus, Ohio. The – University of Texas MD Anderson Cancer Center, Houston, Texas. bition of CDK1 plays a critical role in G2 M checkpoint under normal cell growth and in response to DNA damage or replication stress (15). Note: Supplementary data for this article are available at Clinical Cancer DNA damage or replication stress activates ATM/CHK2 and Research Online (http://clincancerres.aacrjournals.org/). ATR/CHK1 signaling cascades to maintain genome stability and cell Corresponding Author: Terence M. Williams, Ohio State University Wexner viability (13). Activation of CHK1 by ATR in response to various types Medical Center, 460 W. 12th Avenue, Room 492, Columbus, OH 43235. of DNA lesions phosphorylates and stimulates Wee1 activation to Phone: 614-366-2621; Fax: 614-293-4044; E-mail: [email protected] suppress CDK1 activity thereby preventing entry into mitosis (15). Forced cell-cycle progression in the setting of DNA damage perpe- Clin Cancer Res 2020;XX:XX–XX tuates DNA and chromatin damage, and leads to cell death because doi: 10.1158/1078-0432.CCR-19-3373 of irreparable genetic lesions (11). Interestingly, Wee1 expression is Ó2020 American Association for Cancer Research. upregulated in many cancers and associated with the survival of AACRJournals.org | OF1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst March 27, 2020; DOI: 10.1158/1078-0432.CCR-19-3373 Yang et al. xenografts. Our findings suggest that AZD1775 in combination with Translational Relevance radiotherapy may improve the therapeutic outcome of patients with Stage II/III esophageal cancers are commonly treated with esophageal cancer. radiation or chemoradiation, with or without surgery. However, esophageal cancer has very poor prognosis, and preclinical studies have shown esophageal cancer cells are resistant to radiation. The Materials and Methods majority of both esophageal adenocarcinoma and squamous cell Antibodies, chemicals, and cell culture carcinomas harbor mutations in TP53, an important tumor sup- OE33, SK4, FLO1, KYSE30, and AGS cell lines were maintained at – pressor gene that also functions to promote cell-cycle arrest in G1 S 37 Cin5%CO2 in DMEM medium supplemented with 10% FBS after DNA damage from radiation. In this preclinical study, we (Sigma), 1% penicillin/streptomycin (Life Technologies). The detailed target the G2–M cell-cycle checkpoint with AZD1775, a Wee1 cell line information is listed in Supplementary Table S1. AZD1775 was kinase inhibitor, in combination with radiation to enhance ther- obtained under a material transfer agreement from NCI-CTEP apeutic efficacy. We find that in TP53-mutated cells lacking an through AstraZeneca and was dissolved in DMSO (Sigma) and added – effective G1 S checkpoint, AZD1775 markedly radiosensitizes to medium with a final concentration of no more than 0.1% DMSO. esophageal cancer cells to radiation both in cell culture assays and Total CDK1, phospho-CDK1 (Tyr15), phospho-Wee1 (Ser642), phos- animal studies. Our results justify a clinical trial to determine the pho-H2AX (S139), phospho-histone H3 (S10), cyclin A2, cyclin B1, safety and efficacy of combining AZD1775 and radiation in cyclin E1, cyclin E2, and GAPDH primary antibodies were purchased patients with esophageal cancer. from Cell Signaling Technology. Anti-rabbit and anti-mouse second- ary antibodies were purchased from LI-COR Biosciences. AlamarBlue assay and IC50 determination patients with cancer (16–18). Given the pivotal role for Wee1 in AlamarBlue assay was performed according to manufacturer's instruc- the regulation of CDK1 activity, targeting Wee1 has been proposed tions (Roche). Briefly, cells were seeded in 96-well plates in six replicates at for the sensitization of cancer cells to radiotherapy and a density of 2,000 cells per well in 100 mL medium. The next day, the cells chemotherapy (11, 19–21). Large-scale genomic studies have found were treated with AZD1775 at various concentrations. After 72 hours, that esophageal cancer has an extremely high frequency of TP53 alamarBlue reagent was added and incubated at 37C for 4 hours, and mutations, ranging from 44% to 93% (22, 23). Recently, The Cancer absorbance was measured at 490 nm. IC50 was determined using the Genome Atlas (TCGA) demonstrated that TP53 mutations were the nonlinear four-parameter regression function in GraphPad Prism. single most common significantly mutated gene in ESCA, occurring in 71% and 91% of esophageal adenocarcinoma and esophageal Immunoblotting squamous cell carcinoma,
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