Inhibition of Mammalian target of rapamycin by rapamycin causes the regression of carcinogen-induced skin tumor lesions.
OBJECTIVE
The activation of Akt/mammalian target of rapamycin (mTOR) pathway represents a frequent event in squamous cell carcinoma (SCC) progression, thus raising the possibility of using specific mTOR inhibitors for the treatment of SCC patients. In this regard, blockade of mTOR with rapamycin prevents the growth of human head and neck SCC cells when xenotransplanted into immunodeficient mice. However, therapeutic responses in xenograft tumors are not always predictive of clinical anticancer activity.


METHODS
As genetically defined and chemically induced animal cancer models often reflect better the complexity of the clinical setting, we used here a two-step chemical carcinogenesis model to explore the effectiveness of rapamycin for the treatment of skin SCC.


RESULTS
Rapamycin exerted a remarkable anticancer activity in this chemically induced cancer model, decreasing the tumor burden of mice harboring early and advanced tumor lesions, and even recurrent skin SCCs. Immunohistochemical studies on tumor biopsies and clustering analysis revealed that rapamycin causes the rapid decrease in the phosphorylation status of mTOR targets followed by the apoptotic death of cancer cells and the reduction in the growth and metabolic activity of the surviving ones, concomitant with a decrease in the population of cancer cells expressing mutant p53. This approach enabled investigating the relationship among molecular changes caused by mTOR inhibition, thus helping identify relevant biomarkers for monitoring the effectiveness of mTOR inhibition in the clinical setting.


CONCLUSIONS
Together, these findings provide a strong rationale for the early evaluation of mTOR inhibitors as a molecular targeted approach to treat SCC.
Amornphimoltham
Panomwat
P
Oral and Pharyngeal Cancer Branch, National Institute of Craniofacial and Dental Research, NIH, Bethesda, Maryland 20892-4330, USA.
Leelahavanichkul
Kantima
K
Molinolo
Alfredo
A
Patel
Vyomesh
V
Gutkind
J Silvio
JS
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D005260:Female; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D002352:Carrier Proteins; D015127:9,10-Dimethyl-1,2-benzanthracene; D017853:Phosphotransferases (Alcohol Group Acceptor); C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus