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Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours

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An Erratum to this article was published on 04 November 2014

Abstract

Insulin-like growth factor-1 receptor (IGF1R) signalling is implicated in resistance to trastuzumab. However, the benefit of co-targeting HER2 and IGF1R has not been extensively studied, and the relationship between activated IGF1R and clinical response to trastuzumab has not been reported. This study aimed to evaluate the combination of trastuzumab with IGF1R tyrosine kinase inhibitors (TKIs) in a panel of HER2-positive breast cancer cell lines, and to examine the relationship between IGF1R expression and activation and response to trastuzumab in HER2-positive breast cancer patients. The anti-proliferative effects of trastuzumab combined with IGF1R TKIs BMS-536924 or NVP-AEW541 were measured in nine HER2-positive cell lines. IGF1R and phosphorylated IGF1R/insulin receptor (pIGF1R/IR) were measured by immunohistochemistry in 160 tumour samples from trastuzumab-treated patients (ICORG 06-22). The HER2-positive cell lines displayed varying sensitivity to IGF1R TKIs alone (IC50s: 0.7 to >10 μM). However, when combined with trastuzumab, a significantly enhanced effect was observed in five cell lines treated with BMS-536924, and three with NVP-AEW541. While IGF1R levels correlated with reduced response to NVP-AEW541 alone, neither IGF1R nor pIGF1R were predictive of response to BMS-536924 or NVP-AEW541 in combination with trastuzumab. Low HER2 levels correlated with response to BMS-536924 in combination with trastuzumab. Akt levels correlated with improved response to trastuzumab and NVP-AEW541 (P = 0.039). Cytoplasmic IGF1R staining was observed in all tumours, membrane IGF1R was detected in 13.8 %, and pIGF1R/IR was detected in 48.8 %. Although membrane IGF1R staining was associated with larger tumour size (P = 0.041), and lower tumour grade (P = 0.024), no association between IGF1R or pIGF1R/IR and patient survival was observed. In conclusion, while neither IGF1R expression nor activation was predictive of response to trastuzumab, these pre-clinical data provide evidence that co-targeting HER2 and IGF1R may be beneficial in some HER2-amplified breast cancers.

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Acknowledgments

We would like to acknowledge ICORG, the All Ireland Cooperative Oncology Research Group who has sponsored the study (Study no. 06-22). We thank Deirdre McMahon of St. Vincent’s University Hospital for help with TMA processing. This study was supported by the Health Research Board (HRB), Science Foundation Ireland (SFI) and the Cancer Clinical Research Trust (CCRT).

Conflict of interest

John Crown has received research support and speaker’s honoraria from Roche.

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Authors and Affiliations

  1. Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland

    Brigid C. Browne, Alex J. Eustace, Kasper Pedersen, Martina S. J. McDermott, Annemarie Larkin, Stephen Madden, John Crown & Norma O’Donovan

  2. Department of Medical Oncology, St Vincent’s University Hospital, Dublin 4, Ireland

    Jo Ballot, Thamir Mahgoub, Francesco Sclafani & John Crown

  3. Department of Pathology and Laboratory Medicine, St Vincent’s University Hospital, Dublin 4, Ireland

    Susan Kennedy & Michael J. Duffy

  4. Division of Hematology and Oncology, University of California, Los Angeles, USA

    Neil A. O’Brien

  5. Department of Medical Oncology, St James’s Hospital, Dublin 8, Ireland

    John Kennedy

  6. UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin 4, Ireland

    Michael J. Duffy

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  1. Brigid C. Browne
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  2. Alex J. Eustace
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Correspondence to Brigid C. Browne.

Additional information

B. C. Browne and A. J. Eustace contributed equally to this work.

An erratum to this article is available at http://dx.doi.org/10.1007/s10549-014-3176-3.

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Browne, B.C., Eustace, A.J., Kennedy, S. et al. Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours. Breast Cancer Res Treat 136, 717–727 (2012). https://doi.org/10.1007/s10549-012-2260-9

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