Abstract
PurposeThe IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC.MethodsThe protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated.ResultsA high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect.ConclusionsIn addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.
Highlights
Malignant tumors of the adrenal cortex, defined as adrenocortical carcinoma (ACC), are rare but aggressive cancers for which new treatment options are required [1–4]
This study aims at describing the insulin-like growth factor (IGF) pathway in ACC and to explore the in vitro response to the combined treatment with a dual IGF1 receptor (IGF1R)/IR inhibitor and the mTOR inhibitor in an in vitro model of ACC using ACC cell lines
To describe the IGF pathway, the protein expression levels of IGF2, IGF1R and insulin-like growth factor 2 receptor (IGF2R) were evaluated by IHC in the ACC samples
Summary
This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors in in vitro models of ACC. This study aims at describing the IGF pathway in ACC and to explore the in vitro response to the combined treatment with a dual IGF1R/IR inhibitor and the mTOR inhibitor in an in vitro model of ACC using ACC cell lines
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