title: EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex.
abstract: Epidermal growth factor receptor (EGFR)-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1 (nucleotide-binding, lots of leucine-rich repeats-containing protein member X1)-TUFM (Tu translation elongation factor mitochondrial) protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lei
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Kansy
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Cong
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Trivedi
authors.affiliation: Department of Surgery, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: J P-Y
authors.initials: JP
authors.lastname: Ting
authors.affiliation: Department of Restorative Dentistry and Comprehensive Care, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Ferris
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics*; D058990:Molecular Targeted Therapy; D010444:Peptide Elongation Factor Tu / Q000235:genetics*; D000071456:Sequestosome-1 Protein / Q000235:genetics; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000911:Antibodies, Monoclonal; D024101:Mitochondrial Proteins; C527006:NLRX1 protein, human; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C091648:TUFM protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D010444:Peptide Elongation Factor Tu; D000068818:Cetuximab