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


METHODS
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.
Clark
Cheryl
C
Department of Otolaryngology-Head and Neck Surgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Shah
Shivang
S
Herman-Ferdinandez
Lilantha
L
Ekshyyan
Oleksandr
O
Abreo
Fleurette
F
Rong
Xiaohua
X
McLarty
Jerry
J
Lurie
Aubrey
A
Milligan
Edward J
EJ
Nathan
Cherie-Ann O
CO
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D016009:Chi-Square Distribution; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa / Q000378:metabolism*; D009367:Neoplasm Staging; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012189:Retrospective Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D018709:Statistics, Nonparametric; D058570:TOR Serine-Threonine Kinases
D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases