gms | German Medical Science

27th German Cancer Congress Berlin 2006

German Cancer Society (Frankfurt/M.)

22. - 26.03.2006, Berlin

The Rap1/B-Raf signaling complex is a putative therapeutic target in neuroendocrine tumors of the digestive tract

Meeting Abstract

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  • corresponding author presenting/speaker Jörg Schrader - Philipps-Universität, Marburg, Deutschland
  • Dieter Hörsch - Philipps-Universität, Marburg
  • Rudolf Arnold - Philipps-Universität, Marburg

27. Deutscher Krebskongress. Berlin, 22.-26.03.2006. Düsseldorf, Köln: German Medical Science; 2006. DocPE227

The electronic version of this article is the complete one and can be found online at:

Published: March 20, 2006

© 2006 Schrader et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Background: Molecular pathogenesis of digestive neuroendocrine tumors (dNETS) is largely unknown. Recently, the serine-threonine kinase B-Raf was identified as an oncogene in endocrine cancer such as thyroid carcinoma. In endocrine cells, the small G-protein Rap1 stimulates mitogen-activated protein kinase (MAPK) signaling by activating B-Raf.

Aims: We examined the contribution of Rap1 and B-Raf to pathogenesis of dNETS by investigating expression of Rap1 and B-Raf in dNETS and their contribution to MAPK signaling in neuroendocrine cell lines. In addition, we explored the benefit of suppressing B-Raf kinase by the recently developed inhibitor BAY 43-9006 (Sorafenib) on growth as well as apoptosis and MAPK activation in neuroendocrine cell lines.

Methods and results: Expression of Rap1 and B-Raf in dNETS (19 insulinomas, 15 carcinoid tumors and 10 gastrinomas) was examined by immunohistochemistry, which revealed that Rap1 and B-Raf were highly prevalent in the majority of dNETs. Overexpression of Rap1 and B-Raf activated MAPK extra-cellular dependent kinase (ERK) ERK-2 and ERK-dependent transcription factor Elk-1 in neuroendocrine cell lines Bon and INS-1. Suppression of B-Raf by BAY43-9006 (Sorafenib) inhibited growth and induced apoptosis in Bon and INS-1 cells. In addition, BAY 43-9006 suppressed phosphorylation of MAPK ERK1/2 and its upstream kinase MEK1/2 in Bon and INS-1 cells.

Conclusions: These results indicate that Rap1/B-Raf signaling may contribute to pathogenesis of dNETs and provides a promising molecular target for treatment of dNETs.