1. Academic Validation
  2. β2-AR inhibition enhances EGFR antibody efficacy hampering the oxidative stress response machinery

β2-AR inhibition enhances EGFR antibody efficacy hampering the oxidative stress response machinery

  • Cell Death Dis. 2023 Sep 19;14(9):613. doi: 10.1038/s41419-023-06129-9.
Vitale Del Vecchio # 1 Luigi Mele # 1 Sameer Kumar Panda 1 Ibone Rubio Sanchez-Pajares 1 Laura Mosca 2 Virginia Tirino 1 Massimiliano Barbieri 3 Francesca Bruzzese 3 Antonio Luciano 3 Federica Zito Marino 4 Marina Accardo 4 Giovanni Francesco Nicoletti 5 Gianpaolo Papaccio 6 Antonio Barbieri 3 Vincenzo Desiderio 7
Affiliations

Affiliations

  • 1 Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • 2 Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • 3 S.S.D. Sperimentazione Animale, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, Naples, Italy.
  • 4 Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.
  • 5 Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania "L. Vanvitelli", Via L. de Crecchio 6, 80138, Naples, Italy.
  • 6 Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. gianpaolo.papaccio@unicampania.it.
  • 7 Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy. vincenzo.desiderio@unicampania.it.
  • # Contributed equally.
Abstract

The β2-Adrenergic receptor (β2-ARs) is a cell membrane-spanning G protein-coupled receptors (GPCRs) physiologically involved in stress-related response. In many cancers, the β2-ARs signaling drives the tumor development and transformation, also promoting the resistance to the treatments. In HNSCC cell lines, the β2-AR selective inhibition synergistically amplifies the cytotoxic effect of the MEK 1/2 by affecting the p38/NF-kB oncogenic pathway and contemporary reducing the NRF-2 mediated antioxidant cell response. In this study, we aimed to validate the anti-tumor effect of β2-AR blockade and the synergism with MEK/ERK and EGFR pathway inhibition in a pre-clinical orthotopic mouse model of HNSCC. Interestingly, we found a strong β2-ARs expression in the tumors that were significantly reduced after prolonged treatment with β2-Ars inhibitor (ICI) and EGFR mAb Cetuximab (CTX) in combination. The β2-ARs down-regulation correlated in mice with a significant tumor growth delay, together with the MAPK signaling switch-off caused by the blockade of the MEK/ERK phosphorylation. We also demonstrated that the administration of ICI and CTX in combination unbalanced the cell ROS homeostasis by blocking the NRF-2 nuclear translocation with the relative down-regulation of the antioxidant Enzyme expression. Our findings highlighted for the first time, in a pre-clinical in vivo model, the efficacy of the β2-ARs inhibition in the treatment of the HNSCC, remarkably in combination with CTX, which is the standard of care for unresectable HNSCC.

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