Small molecules alter VEGFR and PTEN expression in HPV-positive and -negative SCC: new hope for targeted-therapy.
OBJECTIVE
Prognosis for patients with head and neck squamous cell carcinoma (HNSCC) is poor in most cases and has not improved despite advances in therapy. Novel therapeutic approaches are mandatory in order to improve the situation. Everolimus, an inhibitor of mammalian target of rapamycin, as well as the multi-tyrosine kinase inhibitors sorafenib and sunitinib, has demonstrated a substantial therapeutic effect in various types of human cancer with moderate side-effects. Expression of vascular endothelial growth factor receptor (VEGFR) 1 and 2, and of the tumor-suppressor protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were evaluated in chemonaïve human papillomavirus (HPV)-positive and -negative squamous cell carcinoma (SCC) and after exposure to everolimus, sorafenib or sunitinib.


METHODS
p16-positive CERV196 and p16-negative HNSCC 11A and 14C cells were incubated with different drug concentrations for 48-192 h. Expression of VEGFR1 and -2 as well as PTEN were determined by enzyme-linked immunosorbent assay and was compared to a chemonaïve control.


RESULTS
VEGFR1 and -2, as well as PTEN, were expressed in all three cell lines. Sunitinib, sorafenib and everolimus significantly reduced the expression of VEGFR1 and -2, especially in p16-positive CERV196 cells. Sunitinib appeared to be more effective in reducing VEGFR1 and -2 expression than sorafenib and everolimus. PTEN levels were remarkably lower in HPV-positive CERV196 cells. PTEN expression increased significantly under sunitinib and sorafenib in HNSCC 11A and CERV196 cells. Everolimus, on the other hand, led to a significant decrease of PTEN expression in these cell lines.


CONCLUSIONS
The tested drugs displayed a remarkable anti-angiogenic effect by inhibition of VEGFR1 and -2 expression. Sunitinib and sorafenib were able to increase PTEN expression, which might induce apoptosis of cancer cells. HPV-positive CERV196 cells were characterized by an increased susceptibility to these small-molecule drugs. Further studies are imperative to scrutinize HPV status-dependent differences in drug response and possible implications for future treatment options.
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany christoph.aderhold@umm.de.
Christoph
C
Aderhold
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Anne
A
Faber
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Claudia
C
Umbreit
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Anja
A
Chakraborty
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Andre
A
Bockmayer
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Richard
R
Birk
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Jörg Ulrich
JU
Sommer
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Karl
K
Hörmann
Department of Otorhinolaryngology Head and Neck Surgery, University Hospital Mannheim, Mannheim, Germany.
Johannes David
JD
Schultz
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000821:virology; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D058990:Molecular Targeted Therapy; D051059:PTEN Phosphohydrolase / Q000032:analysis*; D027383:Papillomaviridae / Q000302:isolation & purification*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis* / Q000037:antagonists & inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck
D040262:Receptors, Vascular Endothelial Growth Factor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
PTEN; Tyrosine kinase inhibitor; VEGFR; everolimus; head and neck squamous cell carcinoma; sorafenib; sunitinib