EGF and IGF1 affect sunitinib activity in BP-NEN: new putative targets beyond VEGFR?

Abstract

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.

Evaluation of Spheroid 3D Culture Methods to Study a Pancreatic Neuroendocrine Neoplasm Cell Line

“…The third method was performed as previously described (24, 25). Briefly, 30 μl complete medium containing 2.4 × 10 3 cells were seeded in each well in an ultra low attachment 96-well plate (Corning® 96-well Clear Round Bottom Ultra-Low Attachment Microplate, NY, USA).…”

Exploring Emerging Therapeutic Targets and Opportunities in Neuroendocrine Tumors: Updates on Receptor Tyrosine Kinases

“…In some neuroendocrine tumors, particularly pulmonary carcinoids and a subset of gastrointestinal NETs, increased expression and activation of EGFR have been observed [16]. EGFR-targeting molecules demonstrate efficacy in vitro models of NETs, with erlotinib, a selective EGFR inhibitor, exhibiting activity in reducing cell viability in lung neuroendocrine cell lines and primary cultures [17]. Elevated EGFR expression was observed in highly glycosylated and aggressive pancreatic NETs, correlating with a poor prognosis [18].…”

“…Despite the longstanding awareness of elevated expression levels of IGF-1R and its associated proteins in NET cells, dating back to seminal studies in the early 2000s [23][24][25][26] the precise mechanistic role of IGF-1R in the context of NETs remains tantalizingly elusive. While accumulating evidence underscores the involvement of IGF-1R in mediating responses to therapeutic interventions, including mTOR inhibition [17,27], the functional implications of its activity within NETs are far from straightforward. Compounding the complexity, IGF-1R's potential to form heterodimers with insulin receptors introduces an additional layer of intricacy to its signaling dynamics, warranting careful consideration [28].…”