Novel EGFR ectodomain mutations associated with ligand-independent activation and cetuximab resistance in head and neck cancer.

Autor: Nair S; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Trummell HQ; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Rajbhandari R; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Thudi NK; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Nozell SE; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Warram JM; Department of Otolaryngology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Willey CD; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Yang ES; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Placzek WJ; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Bonner JA; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America., Bredel M; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Feb 18; Vol. 15 (2), pp. e0229077. Date of Electronic Publication: 2020 Feb 18 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0229077
Abstrakt: Epidermal growth factor receptor (EGFR) is a pro-tumorigenic receptor tyrosine kinase that facilitates growth for cancer cells that overexpress the receptor. Monoclonal anti-EGFR antibody Cetuximab (CTX) provides significant clinical benefit in patients with head and neck squamous cell carcinoma (HNSCC). Missense mutations in the ectodomain (ECD) of EGFR can be acquired under CTX treatment and mimic the effect of large deletions on spontaneous untethering and activation of the receptor. Little is known about the contribution of EGFR ECD mutations to EGFR activation and CTX resistance in HNSCC. We identified two concurrent non-synonymous missense mutations (G33S and N56K) mapping to domain I in or near the EGF binding pocket of the EGFR ECD in patient-derived HNSCC cells that were selected for CTX resistance through repeated exposure to the agent in an effort to mimic what may occur clinically. Structural modeling predicted that the G33S and N56K mutants would restrict adoption of a fully closed (tethered) and inactive EGFR conformation while not permitting association of EGFR with the EGF ligand or CTX. Binding studies confirmed that the mutant, untethered receptor displayed reduced affinity for both EGF and CTX but demonstrated sustained activation and presence at the cell surface with diminished internalization and sorting for endosomal degradation, leading to persistent downstream AKT signaling. Our results demonstrate that HNSCC cells can select for EGFR ECD mutations under CTX exposure that converge to trap the receptor in an open, ligand-independent, constitutively activated state. These mutants impede the receptor's competence to bind CTX possibly explaining certain cases of CTX treatment-induced or de novo resistance to CTX.
Competing Interests: James A. Bonner: consultant with Merck Serono Eddy S. Yang: advisory board Strata Oncology, AZ, Bayer, Clovis; preclinical research support from Eli Lilly and Novartis. Please note these two authors do not report conflicts related to this work but opted to disclose the above for completeness.
Databáze: MEDLINE
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