EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells.

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-NH(2)-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.

• Authors: Iris Eke, Lydia Schneider, Claudia Förster, Daniel Zips, Leoni A Kunz-Schughart, Nils Cordes
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 1 Pg. 297-306 (Jan 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23074283 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• RNA, Small Interfering
• Radiation-Sensitizing Agents
• Spag9 protein, mouse
• Mitogen-Activated Protein Kinase 9
• ErbB Receptors
• Cetuximab

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Humanized
• Blotting, Western
• Carcinoma, Squamous Cell (metabolism)
• Cell Culture Techniques (methods)
• Cell Line, Tumor
• Cetuximab
• Drug Resistance, Neoplasm (physiology)
• ErbB Receptors (metabolism)
• Humans
• Immunoprecipitation
• Mice
• Mice, Nude
• Mitogen-Activated Protein Kinase 9 (metabolism)
• Protein Array Analysis
• RNA, Small Interfering
• Radiation-Sensitizing Agents (pharmacology)
• Signal Transduction (physiology)
• Transfection