IGF1R activation and the in vitro antiproliferative efficacy of IGF1R inhibitor are inversely correlated with IGFBP5 expression in bladder cancer

Yann Neuzillet,Isabelle Bernard-Pierrot,Thierry Lebret,Leanne De Koning,Elodie Chapeaublanc,François Radvanyi,Clémentine Krucker

doi:10.1186/s12885-017-3618-5

Abstract

BackgroundThe insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway — insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1–7, IGF2BP1–3) — in bladder cancer and its correlation with IGF1R activation, and the anti-proliferative efficacy of an IGF1R kinase inhibitor in this setting.MethodsWe analyzed transcriptomic data from two independent bladder cancer datasets, corresponding to 200 tumoral and five normal urothelium samples. We evaluated the activation status of the IGF pathway in bladder tumors, by assessing IGF1R phosphorylation and evaluating its correlation with mRNA levels for IGF pathway components. We finally evaluated the correlation between inhibition of proliferation by a selective inhibitor of the IGF1R kinase (AEW541), reported in 13 bladder cancer derived cell lines by the Cancer Cell Line Encyclopedia Consortium and mRNA levels for IGF pathway components.ResultsIGF1R expression and activation were stronger in non-muscle-invasive than in muscle-invasive bladder tumors. There was a significant inverse correlation between IGF1R phosphorylation and IGFBP5 expression in tumors. Consistent with this finding, the inhibition of bladder cell line viability by IGF1R inhibitor was also inversely correlated with IGFBP5 expression.ConclusionThe IGF pathway is activated and therefore a potential therapeutic target for non muscle-invasive bladder tumors and IGFBP5 could be used as a surrogate marker for predicting tumor sensitivity to anti-IGF therapy.

Highlights

The insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer
BrainArray annotation ENTREZG provided one remapped probeset per gene, according to National Center for Biotechnology Information (NCBI) Homo sapiens ENTREZGENE build 36.1.We focused on 16 genes encoding members of the IGF family receptors (INSR, IGF1R, and IGF2R), ligands (INS, IGF1, and IGF2), and binding proteins (IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, IGFBP6, IGFBP7, IGF2BP1, IGF2BP2, and IGF2BP3), referred here to collectively as components of the IGF pathway
Changes in the expression of genes encoding components of the IGF/Insulin growth factor receptor (IGFR) system in bladder cancer We studied changes in the level of expression of 16 genes of the IGF pathway (IGF receptors, ligands, and binding proteins) during bladder tumor progression

Summary

Introduction

The insulin growth factor (IGF) pathway has been proposed as a potential therapeutic target in bladder cancer. We characterized the expression of components of the IGF pathway — insulin growth factor receptors (INSR, IGF1R, IGF2R), ligands (INS, IGF1, IGF2), and binding proteins (IGFBP1–7, IGF2BP1–3) — in bladder cancer and its correlation with IGF1R activation, and the anti-proliferative efficacy of an IGF1R kinase inhibitor in this setting. Proline-rich tyrosine kinase 2 (PTK2B), which is strongly activated by IGF1, has been shown to be critical for IGF1R-dependent motility and invasion and for regulation of the IGF1dependent activation of AKT and MAPK pathways [11]. Activation of the IGF1R/INSR pathway may involve mechanisms different from overexpression of the receptor, such as autocrine stimulation due to the overproduction of IGF2

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Conclusion