Antitumor Activity of Axitinib in Lung Carcinoids: A Preclinical Study

Simple Summary Lung carcinoids (LCs) are categorized as low- and intermediate-grade neuroendocrine tumors. Surgery is effective for localized LCs with a favorable prognosis. However, there is a pressing need for new treatments for unresectable and metastatic LCs. This study explored the potential antitumor effects of axitinib using both in vitro (immortalized cell lines) and in vivo (zebrafish) LC models. Axitinib demonstrated significant antitumor activity by reducing cell viability, inducing cell cycle arrest, and promoting cell death. Moreover, axitinib had a notable impact on crucial processes in tumor progression, including tumor-induced angiogenesis and invasiveness.Abstract Lung carcinoids (LCs) comprise well-differentiated neuroendocrine tumors classified as typical (TCs) and atypical (ACs) carcinoids. Unfortunately, curative therapies remain elusive for metastatic LCs, which account for 25-30% of cases. This study evaluated the antitumor activity of axitinib (AXI), a second-generation tyrosine kinase inhibitor selectively targeting vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, VEGFR-3) in human lung TC (NCI-H727, UMC-11, NCI-H835) and AC (NCI-H720) cell lines. In vitro and in vivo (zebrafish) assays were performed following AXI treatment to gather several read-outs about cell viability, cell cycle, the secretion of proangiogenic factors, apoptosis, tumor-induced angiogenesis and migration. AXI demonstrated relevant antitumor activity in human LC cells, with pronounced effects observed in UMC-11 and NCI-H720, characterized by cell cycle perturbation and apoptosis induction. AXI significantly hindered tumor induced-angiogenesis in Tg(fli1a:EGFP)y1 zebrafish embryos implanted with all LC cell lines and also reduced the invasiveness of NCI-H720 cells, as well as the secretion of several proangiogenic factors. In conclusion, our study provides initial evidence supporting the potential anti-tumor activity of AXI in LC, offering a promising basis for future investigations in mammalian animal models and, eventually, progressing to clinical trials.