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Breast Cancer Research and Treatment

, Volume 136, Issue 3, pp 717–727 | Cite as

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

  • Brigid C. Browne
  • Alex J. Eustace
  • Susan Kennedy
  • Neil A. O’Brien
  • Kasper Pedersen
  • Martina S. J. McDermott
  • Annemarie Larkin
  • Jo Ballot
  • Thamir Mahgoub
  • Francesco Sclafani
  • Stephen Madden
  • John Kennedy
  • Michael J. Duffy
  • John Crown
  • Norma O’Donovan
Preclinical study

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.

Keywords

HER2 Insulin-like growth factor-1 receptor IGF1R Trastuzumab Resistance Breast cancer 

Notes

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.

Supplementary material

10549_2012_2260_MOESM1_ESM.doc (140 kb)
Supplementary material 1 (DOC 140 kb)

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Brigid C. Browne
    • 1
  • Alex J. Eustace
    • 1
  • Susan Kennedy
    • 3
  • Neil A. O’Brien
    • 4
  • Kasper Pedersen
    • 1
  • Martina S. J. McDermott
    • 1
  • Annemarie Larkin
    • 1
  • Jo Ballot
    • 2
  • Thamir Mahgoub
    • 2
  • Francesco Sclafani
    • 2
  • Stephen Madden
    • 1
  • John Kennedy
    • 5
  • Michael J. Duffy
    • 3
    • 6
  • John Crown
    • 1
    • 2
  • Norma O’Donovan
    • 1
  1. 1.Molecular Therapeutics for Cancer Ireland, National Institute for Cellular BiotechnologyDublin City UniversityDublin 9Ireland
  2. 2.Department of Medical OncologySt Vincent’s University HospitalDublin 4Ireland
  3. 3.Department of Pathology and Laboratory MedicineSt Vincent’s University HospitalDublin 4Ireland
  4. 4.Division of Hematology and OncologyUniversity of CaliforniaLos AngelesUSA
  5. 5.Department of Medical OncologySt James’s HospitalDublin 8Ireland
  6. 6.UCD School of Medicine and Medical Science, Conway InstituteUniversity College DublinDublin 4Ireland

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