Molecular dissection of effector mechanisms of <i>RAS</i>-mediated resistance to anti-EGFR antibody therapy

Abstract

// Stefan Kasper 1 , Henning Reis 2 , Sophie Ziegler 1 , Silke Nothdurft 1 , Andre Mueller 1 , Moritz Goetz 2 , Marcel Wiesweg 1 , Jeannette Phasue 1 , Saskia Ting 2 , Sarah Wieczorek 1 , Anna Even 1 , Karl Worm 2 , Michael Pogorzelski 1 , Sandra Breitenbuecher 1 , Johannes Meiler 1 , Andreas Paul 3 , Tanja Trarbach 1, 5 , Kurt Werner Schmid 2 , Frank Breitenbuecher 1 and Martin Schuler 1, 4 1 Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany 2 Institute of Pathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany 3 Department of General, Visceral und Transplantation Surgery, University Hospital Essen, University Duisburg-Essen, 45122 Essen, Germany 4 German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45122 Essen, Germany 5 Present address: Center for Tumor Biology and Integrative Medicine, Hospital Wilhelmshaven, 26389 Wilhelmshaven, Germany Correspondence to: Stefan Kasper, email: stefan.kasper@uk-essen.de Keywords: MAPK, PI3K/AKT, resistance, anti-EGFR antibody, colorectal cancer Received: April 18, 2016&nbsp;&nbsp;&nbsp;&nbsp; Accepted: April 03, 2017&nbsp;&nbsp;&nbsp;&nbsp; Published: April 26, 2017 ABSTRACT 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.