Molecular genetics of cutaneous squamous cell carcinoma: perspective for treatment strategies

Abstract

Cutaneous squamous cell carcinoma (cSCC) represents 20% of all skin cancers. Although primary cSCCs can be successfully treated with surgery, a subset of highly aggressive lesions may progress to advanced disease, representing a public healthcare problem with significant cancer-related morbidity and mortality. A complex network of genes (TP53, CDKN2A, NOTCH1 and NOTCH2, EGFR and TERT) and molecular pathways (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) have been shown to play an important role in the pathogenesis of cSCC. The epigenetic regulation of TP53 and CDKN2A is an attractive therapeutic target for the treatment of cSCC, as well as NOTCH-activating agents capable to restore its tumour-suppressor function. EGFR inhibitors including both monoclonal antibodies (cetuximab and panitumumab) and tyrosine kinase inhibitors (erlotinib, gefitinib and dasatinib) have been used in clinical trials for the treatment of advanced cSCC, achieving only partial clinical benefit. Recently, an immune-modulatory drug (cemiplimab) has been introduced for the treatment of advanced cSCC with good clinical results and a favourable safety profile, while other PD1/PD-L1 inhibitors, either as monotherapy or in combination with targeted therapies, are currently under investigation. This review focuses on molecular findings involved in the pathogenesis of cSCC and their implications for the future development of new treatment strategies. In addition, current and ongoing treatments on targeted therapies and/or immunotherapy are illustrated.JEADV 2020, 34, 932-941 934 Di Nardo et al.

Cutaneous Squamous Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches

“…The inactivation of p53 in cSCC is mainly due to gene mutations or interactions with viral proteins such as HPV E6 [66] (Figure 6a). Missense "hot spots" mutations are mainly characterized by UV-signature (i.e., C > T or CC > TT transitions), which enable keratinocytes to prevent apoptosis and to promote clonal expansion of TP53 mutated cells [66]. The role of p53 in UV-B-induced carcinogenesis has been confirmed in animal models [67].…”

“…Several feedback loops regulate this kinase cascade [65]. ERK act on multiple cytosolic and nuclear targets, including kinases, cytoskeletal protein, and transcription factors [66] (Figure 6C). For instance, ERK regulates the transcriptional activity of ETS1 that, in turn, promotes transcription of several key players of tumor development and progression, including genes involved in cellular proliferation and survival (bcl-2, caspase-1, p16INK4a, p21, p53) and extracellular matrix remodeling and angiogenesis (metalloproteases) [30].…”

MicroRNA-21 Contributes to Cutaneous Squamous Cell Carcinoma Progression via Mediating TIMP3/PI3K/AKT Signaling Axis

“… 27 Moreover, the PI3K/AKT/mTOR pathway was displayed by Nardo et al to play an indispensable role in the pathogenesis of CSCC. 14 A recent study indicated that miR-21 directly targets and inhibits the expression of PTEN (a negative modulator of the PI3K/AKT pathway), and miR-21 inhibition upregulated PTEN expression but impaired the PI3K/AKT pathway, thereby elevating liver cancer cell apoptosis. 28 Furthermore, miR-21 down-regulation causes an impairment in PI3K/AKT pathway activation in Burkitt’s lymphoma.…”

“…Furthermore, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway has been evidenced to be involved in the pathogenesis of CSCC. 14 Notably, another study has proved that the PI3K/AKT serves as a mediator in CSCC cell growth and development. 15 On top of that, the combined interplay of miR-21, TIMP3 and PI3K/AKT pathway in CSCC is lack of explorations.…”

Plattenepithelkarzinom der Haut

“…Die Therapiemöglichkeiten des PEK haben sich kürzlich durch die Immuntherapie deutlich verbessert [16,17]. Weil PEKeinesehrhoheMutationslastaufweisen, wird auch ein gutes Ansprechen auf PD-1/PD-L1-Inhibitoren erwartet [18,19].…”