title: Targeting radioresistant breast cancer cells by single agent CHK1 inhibitor via enhancing replication stress.
abstract: Radiotherapy (RT) remains a standard therapeutic modality for breast cancer patients. However, intrinsic or acquired resistance limits the efficacy of RT. Here, we demonstrate that CHK1 inhibitor AZD7762 alone significantly inhibited the growth of radioresistant breast cancer cells (RBCC). Given the critical role of ATR/CHK1 signaling in suppressing oncogene-induced replication stress (RS), we hypothesize that CHK1 inhibition leads to the specific killing for RBCC due to its abrogation in the suppression of RS induced by oncogenes. In agreement, the expression of oncogenes c-Myc/CDC25A/c-Src/H-ras/E2F1 and DNA damage response (DDR) proteins ATR/CHK1/BRCA1/CtIP were elevated in RBCC. AZD7762 exposure led to significantly higher levels of RS in RBCC, compared to the parental cells. The mechanisms by which CHK1 inhibition led to specific increase of RS in RBCC were related to the interruptions in the replication fork dynamics and the homologous recombination (HR). In summary, RBCC activate oncogenic pathways and thus depend upon mechanisms controlled by CHK1 signaling to maintain RS under control for survival. Our study provided the first example where upregulating RS by CHK1 inhibitor contributes to the specific killing of RBCC, and highlight the importance of the CHK1 as a potential target for treatment of radioresistant cancer cells.
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.|Department of Breast Surgery, Shanxi Academy of Medical Sciences, The Affiliated Shanxi Dayi Hospital of Shanxi Medical University, Shanxi, 030032, PR China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Jinzhi
authors.initials: J
authors.lastname: Lai
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Zhanwen
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Breast Surgery, Shanxi Academy of Medical Sciences, The Affiliated Shanxi Dayi Hospital of Shanxi Medical University, Shanxi, 030032, PR China.
authors.forename: Jinnan
authors.initials: J
authors.lastname: Gao
authors.affiliation: Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Shuming
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Shashank
authors.initials: S
authors.lastname: Gorityala
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Xiahui
authors.initials: X
authors.lastname: Xiong
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.|Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China.
authors.forename: Ou
authors.initials: O
authors.lastname: Deng
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, PR China.
authors.forename: Zhefu
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Augusta University, Augusta, 30912, GA, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Susana
authors.affiliation: Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.|Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Radiation Oncology, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Junran
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors*; D004260:DNA Repair / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; C582547:LY2603618; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011838:Radiation-Sensitizing Agents; D013876:Thiophenes; D014508:Urea; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: CHK1 inhibitor; double strand break repair; homologous recombination; radioresistance; replication stress