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.

Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

“…Adjustments in copy number were to be expected given that they are generally seen to be in greater numbers in cell lines [ 20 ]. The identification of SNVs and CNVs among the cell lines pertaining to the PI3K/AKT/mTOR pathway builds upon previous observations [ 33 , 34 , 35 ], supporting its prognostic utility, as well as being an indicator of therapeutic responsiveness to corresponding selective inhibitors, as assessed by our compound screening.…”

“…Whilst cell cycle and cytoskeleton-targeting drugs were also unsurprisingly highly efficacious in our study [ 48 ], these compounds do not offer the same degree of specificity as PI3K/AKT/mTOR-targeting agents. Interestingly, some PI3K inhibitors produced little to no response against the cell lines, a likely result of isoform specificity that requires further investigation [ 33 ]. The anti-EGFR biologic Cetuximab is sometimes given to patients with advanced cSCC, achieving overall response rates approaching 50% [ 49 ].…”

Regulation of Hematopoietic Stem Cell Fate and Malignancy

“…PDK1 phosphorylates at threonine 308 of PKB and is also known as the AGC kinase; it is an important downstream molecule of the PI3K signaling pathway [146]. PDK1 phosphorylates its targets to regulate cell metabolism, growth, survival, and anti-apoptosis [147][148][149]. PDK1 deletion severely impaired the repopulating potential of HSCs in murine E15.5 fetal liver (FL).…”

PIM Kinases and Their Relevance to the PI3K/AKT/mTOR Pathway in the Regulation of Ovarian Cancer

“…The PI3K/AKT/mTOR signaling pathway is a central regulator of both normal and cancerous cell physiology that is altered in many human cancers [ 21 , 22 , 23 , 24 ]. It controls cell cycle, metabolism, cell survival, motility, chemoresistance, angiogenesis, and genomic instability [ 6 ].…”