Compensatory activation of Akt in response to mTOR and Raf inhibitors - A rationale for dual-targeted therapy approaches in neuroendocrine tumor disease

Several studies have established a link between aberrant PI(3)K-Akt-mTOR- and Ras-Raf-MEK-Erk1/2 signaling and neuroendocrine tumor disease. In this study, we comparatively investigate the antitumor potential of novel small-molecule inhibitors targeting mTOR (RAD001), mTOR/PI(3)K (NVP-BEZ235) and Raf (Ra1265) on human NET cell lines of heterogeneous origin. All inhibitors induced potent antitumor effects which involved the induction of apoptosis and G0/G1 arrest. However, the dual mTOR/P1(3)K inhibitor NVP-BEZ235 was more efficient compared to the single mTOR inhibitor RA0001. Consistently, NVPBEZ235 prevented the negative feedback activation of Akt as observed after treatment with RAD001. Ra1265 inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion, suggesting the existence of a compensatory feedback loop on P13K-Akt signaling. Finally, combined treatment with RAD001 or NVP-BEZ235 and Raf265 was more efficient than single treatment with either kinase inhibitor. Together, our data provide a rationale for dual targeting of PI(3)K-Akt-mTOR- and Ras-Raf-MEKErk1/2 signaling in NET disease. (C) 2010 Elsevier Ireland Ltd. All rights reserved.