Molecular dissection of effector mechanisms of RAS-mediated resistance to anti-EGFR antibody therapy
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Stefan Kasper1, Henning Reis2, Sophie Ziegler1, Silke Nothdurft1, Andre Mueller1, Moritz Goetz2, Marcel Wiesweg1, Jeannette Phasue1, Saskia Ting2, Sarah Wieczorek1, Anna Even1, Karl Worm2, Michael Pogorzelski1, Sandra Breitenbuecher1, Johannes Meiler1, Andreas Paul3, Tanja Trarbach1,5, Kurt Werner Schmid2, Frank Breitenbuecher1 and Martin Schuler1,4
1Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
2Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
3Department of General, Visceral und Transplantation Surgery, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany
4German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122 Essen, Germany
5Present address: Center for Tumor Biology and Integrative Medicine, Hospital Wilhelmshaven, 26389 Wilhelmshaven, Germany
Stefan Kasper, email: [email protected]
Keywords: MAPK, PI3K/AKT, resistance, anti-EGFR antibody, colorectal cancer
Received: April 18, 2016 Accepted: April 03, 2017 Published: April 26, 2017
Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are a mainstay of metastatic colorectal cancer (mCRC) treatment. However, a significant number of patients suffer from primary or acquired resistance. RAS mutations are negative predictors of clinical efficacy of anti-EGFR antibodies in patients with mCRC. Oncogenic RAS activates the MAPK and PI3K/AKT pathways, which are considered the main effectors of resistance. However, the relative impact of these pathways in RAS-mutant CRC is less defined. A better mechanistic understanding of RAS-mediated resistance may guide development of rational intervention strategies. To this end we developed cancer models for functional dissection of resistance to anti-EGFR therapy in vitro and in vivo. To selectively activate MAPK- or AKT-signaling we expressed conditionally activatable RAF-1 and AKT in cancer cells. We found that either pathway independently protected sensitive cancer models against anti-EGFR antibody treatment in vitro and in vivo. RAF-1- and AKT-mediated resistance was associated with increased expression of anti-apoptotic BCL-2 proteins. Biomarkers of MAPK and PI3K/AKT pathway activation correlated with inferior outcome in a cohort of mCRC patients receiving cetuximab-based therapy. Dual pharmacologic inhibition of PI3K and MEK successfully sensitized primary resistant CRC models to anti-EGFR therapy. In conclusion, combined targeting of MAPK and PI3K/AKT signaling, but not single pathways, may be required to enhance the efficacy of anti-EGFR antibody therapy in patients with RAS-mutated CRC as well as in RAS wild type tumors with clinical resistance.
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