Phosphoinositide 3-Kinase-Dependent Signalling Pathways in Cutaneous Squamous Cell Carcinomas

Abstract

Cutaneous squamous cell carcinoma (cSCC) derives from keratinocytes in the epidermis and accounts for 15-20% of all cutaneous malignancies. Although it is usually curable by surgery, 5% of these tumours metastasise leading to poor prognosis mostly because of a lack of therapies and validated biomarkers. As the incidence rate is rising worldwide it has become increasingly important to better understand the mechanisms involved in cSCC development and progression in order to develop therapeutic strategies. Here we discuss some of the evidence indicating that activation of phosphoinositide 3-kinases (PI3Ks)-dependent signalling pathways (in particular the PI3Ks targets Akt and mTOR) has a key role in cSCC. We further discuss available data suggesting that inhibition of these pathways can be beneficial to counteract the disease. With the growing number of different inhibitors currently available, it would be important to further investigate the specific contribution of distinct components of the PI3Ks/Akt/mTOR pathways in order to identify the most promising molecular targets and the best strategy to inhibit cSCC.

Keywords: Akt; PI3K; cutaneous squamous cell carcinoma; mTOR.

Figure 1

Representative diagram of the epidermis. The basement membrane, separating the dermis from the epidermis, and the distinct strata are indicated.

Figure 2

List of the eight mammalian PI3K isoforms and their classification into three distinct classes. For class I PI3Ks only the four catalytic subunits are shown. Their main lipid products are also indicated.

Figure 3

Schematic and simplified representation of the class I PI3Ks/Akt/mTOR pathway, some of the main cellular functions regulated by it, and the main family of inhibitors targeting it.