Cetuximab Attenuates Its Cytotoxic and Radiosensitizing Potential by Inducing Fibronectin Biosynthesis

Iris Eke,Nils Cordes,Katja Storch,Mechthild Krause

doi:10.1158/0008-5472.can-13-0344

Abstract

Inherent and acquired resistance to targeted therapeutics continues to emerge as a major clinical obstacle. For example, resistance to EGF receptor targeting occurs commonly, more so than was expected, on the basis of preclinical work. Given emerging evidence that cancer cell-substrate interactions are important determinants of therapeutic sensitivity, we examined the impact of cell-fibronectin interactions on the efficacy of the EGF receptor antibody cetuximab, which is used widely for lung cancer treatment. Our results revealed the potential for cell-fibronectin interactions to induce radioresistance of human non-small cell lung cancer cells. Cell adhesion to fibronectin enhanced tumor cell radioresistance and attenuated the cytotoxic and radiosensitizing effects of cetuximab. Both in vitro and in vivo, we found that cetuximab treatment led to a remarkable induction of fibronectin biosynthesis. Mechanistic analyses revealed the induction was mediated by a p38-MAPK-ATF2 signaling pathway and that RNAi-mediated inhibition of fibronectin could elevate the cytotoxic and radiosensitizing potential of cetuximab. Taken together, our findings show how cell adhesion blunts cetuximab, which, by inducing fibronectin, generates a self-attenuating mechanism of drug resistance.

Highlights

Molecular therapies have opened a promising novel approach to overcome tumor–type-dependent cancer cell resistance to radio- and chemotherapy [1, 2]
We show that cetuximab-induced cytotoxicity and radiosensitization is reduced when cells are adherent to fibronectin
Cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing GlutaMax-I supplemented with 10% fetal calf serum (FCS; PAA) and 1% non-essential amino acids (PAA) at 37C in a humidified atmosphere containing 10% CO2

Summary

Introduction

Molecular therapies have opened a promising novel approach to overcome tumor–type-dependent cancer cell resistance to radio- and chemotherapy [1, 2]. Overexpressed in lung, head and neck, colorectal, and breast carcinomas as well as glioblastomas and other tumors, the EGF receptor (EGFR) serves as targetable key promoter of tumor growth and progression [3]. Clinical evaluations of these targeting strategies showed differential efficacy mostly falling below expectations from preclinical analysis [5, 6]. In a phase III clinical trial on head and neck squamous cell carcinomas (HNSCC), cetuximab significantly increased locoregional tumor control and overall patient survival in combination with radiotherapy as compared with radiotherapy alone. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Authors' Affiliations: 1OncoRay—National Center for Radiation Research in Oncology; 2Department of Radiation Oncology, Medical Faculty Carl Gustav Carus, Technische Universita€t Dresden; 3German Cancer Consortium (DKTK); 4German Cancer Research Center (DKFZ); and 5Institute of Radiooncology, Helmholtz Center Dresden–Rossendorf, Dresden, Germany

Methods

Results

Conclusion