title: IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin.
abstract: The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs.
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Ciara H
authors.initials: CH
authors.lastname: O'Flanagan
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Sandra
authors.initials: S
authors.lastname: O'Shea
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Amy
authors.initials: A
authors.lastname: Lyons
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Fionola M
authors.initials: FM
authors.lastname: Fogarty
authors.affiliation: Almac Diagnostics, Craigavon, Northern Ireland, UK.
authors.forename: Nuala
authors.initials: N
authors.lastname: McCabe
authors.affiliation: Almac Diagnostics, Craigavon, Northern Ireland, UK.|Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kennedy
authors.affiliation: School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Rosemary
authors.initials: R
authors.lastname: O'Connor
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D009857:Oncogenes; D010766:Phosphorylation; D011719:Pyrazines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C545990:BMS 754807; D014408:Biomarkers, Tumor; C468783:H2AX protein, human; D006657:Histones; C000597236:IGF1R protein, human; D007093:Imidazoles; D011719:Pyrazines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D017451:Receptors, Somatomedin; D011994:Recombinant Proteins; D014227:Triazines; D017526:Receptor, IGF Type 1; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D002945:Cisplatin
keywords: DNA damage; IGF-1R; TKI; breast cancer