ANTI-TUMOUR TREATMENT Clinical relevance of EGFR- and KRAS-status in colorectal cancer patients treated with monoclonal antibodies directed against the EGFR Volker Heinemann * , Sebastian Stintzing, Thomas Kirchner, Stefan Boeck, Andreas Jung Department of Hematology/Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchionini-Street 15, 81377 Munich, Germany article info Article history: Received 13 November 2008 Accepted 17 November 2008 Keywords: Epidermal growth factor receptor EGFR KRAS mutation Cetuximab Panitumumab Colorectal cancer summary The epidermal growth factor receptor (EGFR) plays an important role in tumorigenesis and tumor pro- gression of colorectal cancer (CRC). As a result, the EGFR has evolved as a relevant target in the treatment of metastatic CRC. KRAS serves as a mediator between extracellular ligand binding and intracellular transduction of signals from the EGFR to the nucleus. The presence of activating KRAS mutations has been identified as a potent predictor of resistance to EGFR-directed antibodies such as cetuximab or pani- tumumab. These agents should therefore be applied only in tumors with a wild-type status of the KRAS gene. Further parameters of resistance are lack of EGFR amplification, PTEN loss or BRAF mutation. However, they are less well studied or associated with less consistent data and therefore require prospective anal- yses before integration into clinical decision making. Future studies need to identify patterns of single or multiple mutations to further increase the power of patient selection for anti-EGFR therapy. While molecular parameters help to predict treatment efficacy upfront, skin toxicity has been accepted as an independent predictor of response during exposure to anti-EGFR therapy. Ó 2008 Elsevier Ltd. All rights reserved. Introduction The epidermal growth factor receptor (EGFR) has become an important target of cancer therapy. Specifically, the antibodies cetuximab and panitumumab, which are directed against the EGFR, have proven efficacy in the treatment of metastatic colorec- tal cancer (mCRC). Several reports indicate that an increased gene copy number of EGFR or mutations of genes responsible for down- stream signalling are important determinants of response or resistance to anti-EGFR antibodies. This review analyses the impact of KRAS mutations on the clinical activity of anti-EGFR directed treatment. The underlying hypothesis is that most KRAS mutations cause a gain of function activating the Ras/MAPK path- way. As signal transduction is activated at the level of KRAS pro- teins, upstream inhibition by EGFR-targeted agents becomes ineffective. EGFR-related signal transduction The EGFR constitutes the link between the extracellular space and the intracellular signal transduction which regulates nuclear processes involved in cell growth, differentiation, survival, cell cy- cle progression, angiogenesis, and drug sensitivity. It is a member of the erbB family of receptor tyrosine kinases, which also include erbB2 (HER2/neu), erbB3 (HER3), and erbB4 (HER4). The EGFR- transmembrane protein is composed of three components: an extracellular ligand binding domain, a lipophilic transmembrane domain, and an intracellular tyrosine kinase domain. Apart from erbB2, specific ligands have been identified for each of the erbB receptors. Among these, the epidermal growth factor (EGF) and the transforming growth factor-a (TGF-a) selectively bind to the EGFR. Extracellular ligand binding induces activation of the transmembrane receptors, subsequent homo- or heterodimeriza- tion between the different receptors and intracellular autophos- phorylation at the tyrosine kinase domain which, in turn, activates downstream signalling pathways. 1,2 Several pathways of signal transduction have been identified. Activation of the Ras-Raf-mitogen-activated protein kinase (MAPK) pathway induces phosphoprotein expression of p-MEK and p- ERK1/2. Preclinical and clinical data suggest that MAPK plays a key role in the regulation of cell growth, differentiation, prolifera- tion, apoptosis, and cellular invasiveness. 2,3 EGFR-mediated signalling via PI3 kinase (PI3K) causes activation of AKT, which re- sults in the expression of phosphoproteins such as p-AKT, p-GSK3, and p-P70S6K. The PI3K/AKT pathway is regulated by phosphatase protein homologue to tensin (PTEN) the deficiency of which has been associated with an unsuppressed activation of signal transduction. 0305-7372/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2008.11.005 * Corresponding author. Tel.: +49 89 7095 0; fax: +49 89 7095 2257. E-mail address: Volker.Heinemann@med.uni-muenchen.de (V. Heinemann). Cancer Treatment Reviews 35 (2009) 262–271 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv