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EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1–TUFM protein complex

Oncogene volume 35, pages 4698–4707 (2016)Cite this article

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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.

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Acknowledgements

This work is supported by NIH grants K99 DE024173 (YL), T32 CA060397 (RLF), R01 DE019727 (RLF), P50 CA097190 (RLF), R01 CA182418 (HO) and R21 CA161150 (HO). The UPCI core facilities are supported in part by P30 CA047904. We thank Dr Barton Branstetter for the interpretation of the radiographic findings of the enrolled patients.

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Author notes

  1. Y Lei

    Present address: 6Current Address: Department of Periodontics and Oral Medicine, School of Dentistry; Department of Otolaryngology—Head and Neck Surgery, School of Medicine, Translational Oncology Program and Distributed Health Technologies, U-M Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.,

Authors and Affiliations

  1. Department of Otolaryngology, University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Y Lei, B A Kansy, J Li, L Cong, Y Liu, S Trivedi & R L Ferris

  2. Department of Surgery, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    H Wen

  3. Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    J P-Y Ting

  4. Department of Restorative Dentistry and Comprehensive Care, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    H Ouyang

  5. Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    R L Ferris

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Competing interests

Dr Ferris‘ work is supported, in part, by Bristol-Myers Squibb, AZ/Medimmune. He serves on the Advisory Boards for Cetuximab (Bristol-Myers Squibb and Lilly) and Panitumumab (Amgen).

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Lei, Y., Kansy, B., Li, J. et al. EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1–TUFM protein complex. Oncogene 35, 4698–4707 (2016). https://doi.org/10.1038/onc.2016.11

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