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

Kathrin Zitzmann; Janina von Rüden; Stephan Brand; Burkhard Göke; Jennifer Lichtl; Gerald Spöttl; Christoph J Auernhammer

doi:10.1016/j.canlet.2010.02.018

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

Cancer Lett. 2010 Sep 1;295(1):100-9. doi: 10.1016/j.canlet.2010.02.018. Epub 2010 Mar 30.

Authors

Kathrin Zitzmann¹, Janina von Rüden, Stephan Brand, Burkhard Göke, Jennifer Lichtl, Gerald Spöttl, Christoph J Auernhammer

Affiliation

¹ Department of Internal Medicine II, University-Hospital Munich-Grosshadern, University of Munich, Marchioninistr.15, 81377 Munich, Germany.

PMID: 20356670
DOI: 10.1016/j.canlet.2010.02.018

Abstract

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 (Raf265) 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/PI(3)K inhibitor NVP-BEZ235 was more efficient compared to the single mTOR inhibitor RAD001. Consistently, NVP-BEZ235 prevented the negative feedback activation of Akt as observed after treatment with RAD001. Raf265 inhibited Erk1/2 phosphorylation but strongly induced Akt phosphorylation and VEGF secretion, suggesting the existence of a compensatory feedback loop on PI3K-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-MEK-Erk1/2 signaling in NET disease.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Dose-Response Relationship, Drug
Everolimus
Extracellular Signal-Regulated MAP Kinases / metabolism
Feedback, Physiological / drug effects
G1 Phase / drug effects
Humans
Imidazoles / pharmacology
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
MAP Kinase Signaling System / drug effects
Neuroendocrine Tumors / drug therapy*
Neuroendocrine Tumors / metabolism*
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors
Phosphorylation
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism*
Pyrimidines / pharmacology
Pyrroles / pharmacology
Quinolines / pharmacology
Signal Transduction / drug effects*
Sirolimus / analogs & derivatives*
Sirolimus / pharmacology
TOR Serine-Threonine Kinases
Vascular Endothelial Growth Factor A / metabolism
raf Kinases / antagonists & inhibitors*
raf Kinases / metabolism

Substances

Antineoplastic Agents
Imidazoles
Intracellular Signaling Peptides and Proteins
NVP-AEW541
Phosphoinositide-3 Kinase Inhibitors
Pyrimidines
Pyrroles
Quinolines
Vascular Endothelial Growth Factor A
Everolimus
MTOR protein, human
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases
raf Kinases
Extracellular Signal-Regulated MAP Kinases
dactolisib
Sirolimus