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

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.