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Teasing out the best molecular marker in the AKT/mTOR pathway in head and neck squamous cell cancer patients

Authors

  • Cheryl Clark PhD,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Feist-Weiller Cancer CenterLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Shivang Shah MD, MPH,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Lilantha Herman-Ferdinandez MD,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Oleksandr Ekshyyan PhD,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Feist-Weiller Cancer CenterLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Fleurette Abreo MD, FASCP,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Department of Pathology, Louisiana State University Health Sciences CenterShreveport, Louisiana, U.S.A.
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  • Xiaohua Rong MS,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Feist-Weiller Cancer CenterLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Jerry McLarty MS, PhD,

    1. Feist-Weiller Cancer CenterLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
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  • Aubrey Lurie MD, FCAP,

    1. Overton Brooks VA Medical Center, Shreveport, Louisiana, U.S.A.
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  • Edward J. Milligan MD,

    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Overton Brooks VA Medical Center, Shreveport, Louisiana, U.S.A.
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  • Cherie-Ann O. Nathan MD, FACS

    Corresponding author
    1. Department of Otolaryngology–Head and Neck SurgeryLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    2. Feist-Weiller Cancer CenterLouisiana State University Health Sciences Center, Shreveport, Louisiana, U.S.A.
    3. Overton Brooks VA Medical Center, Shreveport, Louisiana, U.S.A.
    • Professor and Vice-Chairman, Dept. of Otolaryngology–Head and Neck Surgery, Louisiana State University Health Sciences Center, Director of Head and Neck Surgical Oncology, Feist-Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA 71130-3932
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  • This work was supported by National Institutes of Health grant R01 CA 102363-01 to Dr. Cherie-Ann O. Nathan. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Abstract

Objectives/Hypothesis:

No reliable molecular biomarker is currently available for clinical application in the management of head and neck cancer patients. The AKT/mTOR pathway is activated in 90% to 100% of head and neck squamous cell cancer (HNSCC) and could be promising biomarkers closely linked to cancer incidence.

Study Design:

Retrospective study of HNSCC and non-cancer patients.

Methods:

Oral mucosa from noncancer patients were compared to HNSCC tumors and junctional zone mucosa. The candidate biomarkers mTOR, AKT, 4EBP1, and S6 kinase, signaling components upstream and downstream of mTOR that appear dysregulated in HNSCC, were evaluated using immunohistochemistry (IHC) and Western blot analysis.

Results:

Expression of phosphorylated AKT and phosphorylated mTOR were significantly higher in cancer patient tumors compared to noncancer oral mucosa samples (P = .004 and P = .026, respectively) by Western blot analysis. Expression of p-mTOR and p-4EBP1 were higher in patient junctional zones compared to tumors (p = 0.017 and p = 0.022, respectively) and no difference in p-AKT or p-S6 expression in HNSCC patients' junctional zone compared to tumors. IHC-demonstrated p-mTOR expression was 81.9% sensitive and 100% specific in differentiating cancer from noncancer mucosa, whereas p-4EBP1 expression by IHC was only 50.0% sensitive and 95.5% specific in differentiating normal mucosa from HNSCC (P < .01).

Conclusions:

Phosphorylated mTOR appears to be a reliable biomarker by both Western blot analysis (P = .026) and IHC in human head and neck cancer (P < .001). Moreover, phosphorylated AKT, which is immediately upstream of mTOR, is a potential biomarker that should be further studied. Clinical trials with mTOR inhibitors are being evaluated for HNSCC, and selecting patients that are likely to respond to these inhibitors requires identifying and validating predictive biomarkers of response.

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