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Dependence of Wilms tumour cells on signalling through IGF1R in an orthotopic xenograft model targetable by specific receptor inhibition

Bielen, Aleksandra and Box, Gary and Perryman, Lara and Bjerke, Lynn and Popov, Sergey and Jamin, Yann and Jury, Alexa and Valenti, Melanie and de Haven Brandon, Alexis and Martins, Vanessa and Romanet, Vincent and Jeay, Sebastien and Raynaud, Florence and Hofmann, Francesco and Robinson, Simon and Eccles, Suzanne and Jones, Chris (2012) Dependence of Wilms tumour cells on signalling through IGF1R in an orthotopic xenograft model targetable by specific receptor inhibition. PNAS. ISSN 0027-8424

Abstract

We have previously demonstrated an increased DNA copy number and expression of IGF1R to be associated with poor outcome in Wilms tumours. In order to determine whether inhibiting this receptor may be a useful therapeutic strategy, we tested the in vitro efficacy in a panel of Wilms tumour cell lines. Both genetic and pharmacological targeting resulted in an inhibition of downstream signalling through PI3- and MAP-kinase, G1 cell cycle arrest, and cell death, with drug efficacy dependent on the levels of phosphorylated-IGF1R. These effects were further associated with specific gene expression signatures reflecting pathway inhibition, and conferred a chemosensitisation with both doxorubicin and topotecan. In the in vivo setting, subcutaneous xenografts more closely took on the appearance of malignant rhabdoid tumours, rather than Wilms, and treatment with an IGF1R inhibitor showed no discernable antitumour activity, nor downstream pathway inactivation. By contrast, Wilms tumour cells established within the kidney harboured significantly elevated IGF-mediated signalling and were significantly diminished upon treatment with the small molecule inhibitor, in common with pathway ablation. Due to the paracrine effects of enhanced IGF2 expression in Wilms tumour, this disease may be acutely dependent on signalling through the IGF1-receptor, and thus treatment strategies aimed at its inhibition may be useful in the clinic. Such results may be missed if only ectopic models are considered due to an imperfect recapitulation of the specific tumour microenvironment.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4266

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