EGFR/JIP-4/JNK2 Signaling Attenuates Cetuximab-Mediated Radiosensitization of Squamous Cell Carcinoma Cells
Open Access
- 1 January 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 73 (1), 297-306
- https://doi.org/10.1158/0008-5472.can-12-2021
Abstract
EGF receptor (EGFR) promotes tumor growth as well as radio- and chemoresistance in various human malignancies including squamous cell carcinomas (SCC). In addition to deactivation of prosurvival signaling, cetuximab-mediated EGFR targeting might concomitantly induce self-attenuating signaling bypasses. Identification of such bypass mechanisms is key to improve the efficacy of targeted approaches. Here, we show great similarity of EGFR signaling and radiation survival in cetuximab-treated SCC cells grown in a more physiologic three-dimensional extracellular matrix and as tumor xenografts in contrast to conventional monolayer cell cultures. Using phosphoproteome arrays, we observed strong induction of JNK2 phosphorylation potentially resulting from cetuximab-inhibited EGFR through c-jun-NH2-kinase (JNK)-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometric approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacologic JNK2 inhibition enhanced cetuximab efficacy and tumor cell radiosensitivity. Our findings add new facets to EGFR signaling and indicate signaling bypass possibilities of cancer cells to improve their survival on cetuximab treatment. By deactivation of cetuximab–self-attenuating JNK2-dependent signaling, the cytotoxicity, and radiosensitizing potential of cetuximab can be augmented. Cancer Res; 73(1); 297–306. ©2012 AACR.Keywords
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This publication has 39 references indexed in Scilit:
- Diverse effects of combined radiotherapy and EGFR inhibition with antibodies or TK inhibitors on local tumour control and correlation with EGFR gene expressionRadiotherapy and Oncology, 2011
- Dual targeting of EGFR and focal adhesion kinase in 3D grown HNSCC cell culturesRadiotherapy and Oncology, 2011
- Understanding resistance to EGFR inhibitors—impact on future treatment strategiesNature Reviews Clinical Oncology, 2010
- Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung CancerJournal of Clinical Oncology, 2010
- ErbB receptors and signaling pathways in cancerCurrent Opinion in Cell Biology, 2009
- Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR familyJCI Insight, 2008
- Epidermal growth factor receptor inhibitors for radiotherapy: biological rationale and preclinical resultsJournal of Pharmacy and Pharmacology, 2008
- Epidermal Growth Factor Receptor Gene Amplification Is Acquired in Association with Tumor Progression of EGFR-Mutated Lung CancerCancer Research, 2008
- Different classes of EGFR inhibitors may have different potential to improve local tumour control after fractionated irradiation: a study on C225 in FaDu hSCCRadiotherapy and Oncology, 2005
- Combined Modality Therapy of A431 Human Epidermoid Cancer Using Anti-EGFr Antibody C225 and RadiationCancer Biotherapy & Radiopharmaceuticals, 1999