title: Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy.
abstract: BRCA1, a key factor in homologous recombination (HR) repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n = 1602 sporadic and n = 50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n = 1952 and n = 249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p < 0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps < 0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy.
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Nada
authors.initials: N
authors.lastname: Albarakati
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Doherty
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Roslin
authors.initials: R
authors.lastname: Russell
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Moseley
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Christina
authors.initials: C
authors.lastname: Perry
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Arvind
authors.initials: A
authors.lastname: Arora
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Nouf
authors.initials: N
authors.lastname: Alsubhi
authors.affiliation: Academic Haematology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Seedhouse
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Emad A
authors.initials: EA
authors.lastname: Rakha
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.affiliation: School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham NG11 8NS, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Ball
authors.affiliation: Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.affiliation: Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham NG51PB, UK; Department of Oncology, Nottingham University Hospitals, Nottingham NG51PB, UK. Electronic address: srinivasan.madhusudan@nottingham.ac.uk.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Madhusudan
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D015331:Cohort Studies; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015996:Survival Rate
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D002945:Cisplatin
keywords: ATM; BRCA1; Base excision repair; Chemopotentiation; Cisplatin; DNA-PK; Small molecule inhibitors; Synthetic lethality