Oncotarget

Research Papers:

IGF-1R inhibition sensitizes breast cancer cells to ATM-related kinase (ATR) inhibitor and cisplatin

Ciara H. O’Flanagan, Sandra O’Shea, Amy Lyons, Fionola M. Fogarty, Nuala McCabe, Richard D. Kennedy and Rosemary O’Connor _

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Oncotarget. 2016; 7:56826-56841. https://doi.org/10.18632/oncotarget.10862

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Abstract

Ciara H. O’Flanagan1,*, Sandra O’Shea1,*, Amy Lyons1, Fionola M. Fogarty1, Nuala McCabe2, Richard D. Kennedy2,3, Rosemary O’Connor1

1School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland

2Almac Diagnostics, Craigavon, Northern Ireland, UK

3Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, Northern Ireland, UK

*Joint authorship

Correspondence to:

Rosemary O’Connor, email: r.oconnor@ucc.ie

Keywords: IGF-1R, DNA damage, breast cancer, TKI

Received: April 11, 2016    Accepted: July 10, 2016    Published: July 27, 2016

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.


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