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Inhibition of IGF1R activity enhances response to trastuzumab in HER-2 positive breast cancer cells

Browne, BC, Crown, J, Venkatesan, N, Duffy, MJ, Clynes, M, Slamon, D, O'Donovan, N and Jeay, Sebastien (2010) Inhibition of IGF1R activity enhances response to trastuzumab in HER-2 positive breast cancer cells. Annals of Oncology.


BACKGROUND: Although trastuzumab has improved the prognosis for HER-2 positive breast cancer, not all HER-2 positive breast tumours respond to trastuzumab treatment and those that initially respond frequently develop resistance. Insulin-like growth factor-1 receptor (IGF1R) signalling has been previously implicated in trastuzumab resistance. We tested IGF1R inhibition to determine if dual targeting of HER-2 and IGF1R improves response in cell line models of acquired trastuzumab resistance.
METHODS: HER-2, IGF1R, phospho-HER-2, and phospho-IGF1R levels were measured by ELISA in parental and trastuzumab-resistant SKBR3 and BT474 cells. IGF1R signalling was targeted in these cells using siRNA and the tyrosine kinase inhibitor NVP-AEW541.
RESULTS: IGF1R levels were significantly increased in the trastuzumab resistant model, SKBR3/Tr, compared to the parental SKBR3 cell line. In both the SKBR3/Tr and BT474/Tr cell lines, inhibition of IGF1R expression with siRNA or inhibition of tyrosine kinase activity by NVP-AEW541 significantly increased response to trastuzumab. The dual targeting approach also improved response in the parental SKBR3 cells but not in the BT474 parental cells.
CONCLUSIONS: Our results confirm that IGF1R inhibition improves response to trastuzumab in resistant HER-2 positive breast cancer cells, and also suggest that dual targeting of IGF1R and HER-2 may improve response in some trastuzumab-sensitive cells.

Item Type: Article
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Additional Information: Sebastien Jeay is Novartis contact not author of manuscript! author can archive post-print (ie final draft post-refereeing); Publisher version cannot be used except for Nucleic Acids Research articles
Keywords: Breast cancer, HER-2, Herceptin, IGF1R, NVP-AEW541, trastuzumab
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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