Epidermal growth factor pathway as a possible target in the medical therapy of bronchial carcinoids

Abstract

Bronchial carcinoids (BC) are rare tumors originating from endocrine cells dispersed in the respiratory epithelium. Currently, the main BC treatment is surgery, that can be curative in most of the cases, but is not feasible for large, infiltrating and metastatic disease. In these settings, medical therapy is often tried, being mainly represented by chemotherapy and radiation in the attempt to reduce tumor mass, while somatostatin analogues are employed for symptomatic control. Therefore it is important to identify new therapeutic targets and new molecules capable of providing adequate medical treatment for patients with BC for which surgical removal is not feasible. Growth factors which are important in experimental models of neuroendocrine tumors include epidermal growth factor (EGF), transforming growth factor (TGF) α, TGFβ. EGF and TGFα bind to the EGF receptor to stimulate the PI3K/RAS/RAF/MAPK pathway, leading to the transcription of genes associated with cell proliferation, invasion and metastasis. Our aim is to evaluate the effects of Sunitinib, a multi-targeted receptor tyrosine kinase (RTK) inhibitor, and NVP-BEZ235, a PI3K/mTOR inhibitor, on human primary BC cells cultures in order to verify the involvement of the EGF pathway in regulating crucial cellular processes. Human BC primary cultures were treated with Sunitinib or NVP-BEZ235, alone or in combination with EGF. EGFR expression, cell viability and caspase 3/7 activation were evaluated. By immunofluorescences we found that EGFR is expressed in all primary cultures. In addition, 100 nM NVP-BEZ235 and 10 μM Sunitinib inhibit cell viability by 30 and 20% (P<0.01), respectively. Both NVP-BEZ 235 and Sunitinib promote apoptosis (100%). 100 ng/ml EGF impairs the antiproliferative and pro-apoptotic effects of both Sunitinib and NVP-BEZ 235. These data suggest a possible role for EGFR pathway as molecular target in the medical treatment of BC. Further studies are necessary to understand the molecular basis of this mechanism