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Giulia Bresciani Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

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Angeliki Ditsiou Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK

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Chiara Cilibrasi Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK

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Viviana Vella Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK

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Federico Rea Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy

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Marco Schiavon Department of Cardiac, Thoracic and Vascular Sciences, University of Padua, Padua, Italy

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Narciso Giorgio Cavallesco Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

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Georgios Giamas Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK

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Maria Chiara Zatelli Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy

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Teresa Gagliano Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, UK

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Broncho-pulmonary neuroendocrine neoplasms (BP-NENs) are neoplasms orphan of an efficient therapy. Available medical treatments derived from clinical trials are not specific for the management of this malignancy. Sunitinib is a multi-receptor tyrosine-kinases (RTKs) inhibitor that has already shown its efficacy in NENs, but there are no available data about its action in BP-NENs. Therefore, our aim was to understand the effects of RTKs inhibition promoted by sunitinib in order to evaluate new putative targets useful in malignancy treatment. Since our results underlined a role for EGFR and IGF1R in modulating sunitinib antiproliferative action, we investigated the effects of erlotinib, an EGFR inhibitor, and linsitinib, an IGF1R inhibitor, in order to understand their function in regulating cells behaviour. Cell viability and caspase activation were evaluated on two immortalised human BP-NEN cell lines and primary cultures. Our results showed that after treatment with sunitinib and/or IGF1, EGF and VEGF, the antiproliferative effect of sunitinib was counteracted by EGF and IGF1 but not by VEGF. Therefore, we evaluated with AlphaScreen technology the phosphorylated EGFR and IGF1R levels in primary cultures treated with sunitinib and/or EGF and IGF1. Results showed a decrease of p-IGF1R after treatment with sunitinib and an increase after co-treatment with IGF1. Then, we assessed cell viability and caspase activation on BP-NEN cell lines after treatment with linsitinib and/or erlotinib. Results demonstrate that these two agents have a stronger antiproliferative effect compared to sunitinib. In conclusion, our results suggest that IGF1R and EGF1R could represent putative molecular targets in BP-NENs treatment.

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