Oral mTOR Inhibition Limits And Reduces Actinic Keratosis And Cutaneous Squamous Cell Carcinoma In A UVB-Induced Mouse Model

Abstract

ABSTRACTActinic keratosis (AK) is a skin disease that is characterized by clinical and subclinical cutaneous lesions in sun-exposed areas. It is a considerable burden due to its high occurrence in middle-aged and older populations, as well as its propensity to progress to invasive cutaneous squamous cell carcinoma. The mammalian target of rapamycin (mTOR) pathway is critical in carcinogenesis and tumor development, and it has been shown to be over-activated during skin tumorigenesis, particularly upon ultraviolet (UV) radiation exposure, the key risk factor for AK. However, the ability of mTOR inhibitors to treat AK is not well documented. Herein, we evaluated the effect of oral mTOR inhibitorsin vitroandin vivoand found that mTOR inhibitors lower keratinocyte cell proliferationin vitroand both clear and prevent AK and cutaneous squamous cell carcinoma (cSCC) in a UV-B induced SKH1 hairless mouse model of disease. mTOR inhibition reduced the number and size of skin lesions and the frequency of cSCC, resulting in a considerable reduction in disease severity. mTOR inhibition prevented lesion occurrence in areas of field cancerization, without affecting epidermal thickness, keratinocyte proliferationin vivo, or the presence of p53+ cells. Our findings indicate that, when appropriately dosed, oral mTOR inhibitors provide a safe home-based systemic treatment alternative with significant benefits to patients over current topical treatment options.