EGFR/JIP-4/JNK2 signaling attenuates Cetuximab-mediated radiosensitization of squamous cell carcinoma cells
Menée sur des cellules de carcinome épidermoïde et à l'aide de xénogreffes, cette étude montre que l'inhibition de la voie de signalisation EGFR/JIP-4/JNK2 peut augmenter l'efficacité du cetuximab pour sensibiliser les cellules tumorales aux rayonnements ionisants
Epidermal growth factor 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 pro-survival 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 physiological three-dimensional (3D) 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 JNK-interacting protein-4 (JIP-4), which was identified using an immunoprecipitation-mass spectrometry approach. Inhibition of this signaling bypass by JIP-4 or JNK2 knockdown or pharmacological 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 upon Cetuximab treatment. By deactivation of Cetuximab-self-attenuating, JNK2-dependent signaling, the cytotoxicity and radiosensitizing potential of Cetuximab can be augmented.