The role of SRC family kinases in neuroendocrine tumors.

Dear Sir: We read with great interest the paper by Gaur et al,1 describing the identification of a stem cell population in neuroendocrine tumors (NETs), named by the authors neuroendocrine cancer stem cells (N-CSC), through their ALDH activity as evaluated by the Aldefluor assay. The authors presented convincing evidence about the stemness properties of these cells, as suggested by their in vitro and in vivo self-renewal capacity, particularly by their ability of anchorage-independent growth and tumor growth initiation. They also aimed at characterizing potentially “druggable” pathways in these cells, and found that the Src and mammalian target of rapamycin (mTOR) pathways are active in N-CSC. The authors focused their study on the Src pathway and found that targeting Src inhibited the growth both of NCSCs cells in vitro, and of tumors derived from them in vivo. The Src pathway has, therefore, been discussed as a potential novel target with therapeutic potential for NETs. We congratulate with the authors for the excellent work, and we would like to further discuss the potential role of Src family kinases (SFKs) inhibitors for the clinical treatment of NETs. The US Food and Drug Administration has recently approved both the mTOR inhibitor everolimus, and the multityrosine kinase inhibitor sunitinib, for the treatment of progressive, unresectable, locally advanced or metastatic pancreatic endocrine tumors.2 From a molecular viewpoint, he possible limitations of such clinical options include the apacity of cancer cells to develop escape pathways that voke prosurvival feedback responses, and the existence of ross-talk between different molecular pathways which have ot been explored in this cancer type. The activation of scape pathways in tumor cells exposed to targeted therapies as raised interest in the development of combined treatents implying either a “vertical blockage,” targeting several teps in the same pathways (ie, PI3K and mTOR, or vascular ndothelial growth factor and hypoxia-inducible factors), or “horizontal blockage” targeting distinct molecular pathays at the same time, which may converge on the same layer in the cell. However, there are still very few preclinical tudies evaluating these approaches in NETs. The finding that both mTOR and Src pathways are ctivated in these N-CSC, recall some recent evidence that uggested a possible link between SFKs activity and the TOR pathway.3 Moreover, it has been previously demnstrated that SFKs are overexpressed in NETs,4 and that he inhibition of their activity impairs adhesion, spreadng and migration of pancreatic endocrine tumor cells.5 In a more recent study, the possible link between the SFK and mTOR pathways in NETs has been further explored,6 with findings suggesting a novel role for SFKs n controlling the mTOR activity in pancreatic endocrine umor cells. In particular, it was found that SFKs couple he event of cell adhesion and spreading with an increase n mTOR activity. Activation of mTOR by SFKs leads to TOR-dependent activation of translation of a subset of RNAs for cell-cycle proteins. Moreover, the concomitant nhibition of SFK and mTOR activities strongly impaired ET cell growth, compared with the effect exerted by the ingle agents. Of note, although treatment with the TOR inhibitor everolimus triggered the activation of a urvival response dependent on PI3K/AKT signaling, the imultaneous inhibition of SFKs blocked the activation of his unwanted escape signal. We believe that such findings, together with these of aur and colleagues, strengthen the interest on the role of rc in NETs, and suggest the need for further preclinical tudies with SFK inhibitors in animal models of NETs, nd the possible consideration of such drugs for phase I linical trials in patients with this particular cancer type.