Oncotarget

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Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance

Markus Morkel _, Pamela Riemer, Hendrik Bläker and Christine Sers

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Oncotarget. 2015; 6:20785-20800. https://doi.org/10.18632/oncotarget.4750

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Abstract

Markus Morkel1, Pamela Riemer1,2, Hendrik Bläker2,3, Christine Sers1,2

1Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin 10117, Germany

2DKTK, German Consortium for Translational Cancer Research, Partner Site Berlin and DKFZ, German Cancer Research Center, D-63170 Heidelberg, Germany

3Charité Universitätsmedizin Berlin, Institute of Pathology, Berlin 10117, Germany

Corresponding to:

Christine Sers, e-mail: christine.sers@charite.de

Keywords: KRAS, BRAF, colorectal cancer, signaling, therapy

Received: May 07, 2015     Accepted: July 17, 2015     Published: July 30, 2015

ABSTRACT

Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.


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