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

Browne, Brigid / C and Eustace, Alex / J and Kennedy, Susan and O'Brien, Neil / A and Pedersen, Kasper and Larkin, Annemarie and Ballot, Jo and Mahgoub, Thamir and Sclafani, Francesco and Madden, Stephen and Kennedy, John and Duffy, Michael / J and Crown, John and O'Donovan, Norma (2012) Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours. Breast Cancer Res Treat, 136 (3). pp. 717-727. ISSN 0167-6806

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-positve 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), and were related to clinicopathological parameters and survival. The HER2-positve cell lines displayed relatively low sensitivity to IGF1R TKIs alone (IC50s: 0.7 to >10 μM). However, when combined with trastuzumab, a significantly enhanced effect was observed in six of nine cells lines treated with BMS-36924 or NVP-AEW541. Yet, neither IGF1R nor pIGF1R were predictive of response to BMS-536924 or NVP-AEW541 alone, or in combination with trastuzumab. Cytoplasmic IGF1R staining was observed in all tumours, membrane IGF1R was detected in 13.8 % (22/160), and pIGF1R/IR was detected in 48.8 % (78/160). Although membrane IGF1R staining was associated with larger tumour size (p = 0.041), younger age at diagnosis (p = 0.048), 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; the identification of accurate biomarkers of IGF1R signalling will help to select patients most likely to benefit.

Item Type: Article
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Keywords: HER2; insulin-like growth factor-1 receptor; IGF1R; trastuzumab; resistance; breast cancer
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6507

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