title: Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy.
abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.
authors.affiliation: Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Gangnam-Gu, Seoul 135-710, South Korea.
authors.forename: Heekyoung
authors.initials: H
authors.lastname: Yang
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Juyoun
authors.initials: J
authors.lastname: Jin
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Choi
authors.forename: Ho Jun
authors.initials: HJ
authors.lastname: Seol
authors.forename: Jung-Il
authors.initials: JI
authors.lastname: Lee
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Hae Yong
authors.initials: HY
authors.lastname: Yoo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000532:radiotherapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D017353:Gene Deletion; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D013876:Thiophenes / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013876:Thiophenes; D014508:Urea; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse