title: WEE1 inhibition targets cell cycle checkpoints for triple negative breast cancers to overcome cisplatin resistance.
abstract: Cisplatin is one of the most commonly used therapeutic drugs for cancer therapy, yet prolonged cisplatin treatment frequently results in drug resistance. To enhance therapeutic effect of cisplatin, we conducted a high throughput screening using a kinase library containing 704 kinases against triple negative breast cancer (TNBC) cells. We demonstrated that cisplatin activates ATR, CHK1 and WEE1, which shut down DNA replication and attenuate cisplatin induced-lethality. WEE1 inhibition sensitizes TNBCs and cisplatin resistant cancer cells to cisplatin-induced lethality, because it not only impairs DNA replication checkpoint more profoundly than inhibition of ATR or CHK1, but also defects G2-M cell cycle checkpoint. Finally, we demonstrated that combined cisplatin treatment and WEE1 inhibition synergistically inhibits xenograft cancer growth accompanied by markedly reduced expression of TNBC signature genes. Thus targeting DNA replication and G2-M cell cycle checkpoint simultaneously by cisplatin and WEE1 inhibition is promising for TNBCs treatment, and for overcoming their cisplatin resistance.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA.
authors.forename: Hongping
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Shao
authors.affiliation: Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, USA.
authors.forename: Scots
authors.initials: S
authors.lastname: Martin
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA.|Faculty of Health Sciences, University of Macau, Macau SAR, China.
authors.forename: Chu-Xia
authors.initials: CX
authors.lastname: Deng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1 / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D034622:RNA Interference; D000072020:Synthetic Lethal Mutations / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D000071877:Checkpoint Kinase 1; D002945:Cisplatin