Development of gene expression inhibitors for the treatment of cutaneous carcinomas

Abstract

Cutaneous carcinoma is one of the most common cancers worldwide, with rising incidence and mortality rates, especially among white Caucasians. It primarily includes non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC), which together account for over 90% of all skin cancers. The main cause is the abnormal proliferation of skin cells due to genetic mutations and environmental damage [Citation1]. Basal cell carcinoma (BCC) arises from mutations in the Ptch1 tumor suppressor gene caused by UV-radiations, leading to dysregulated hedgehog signaling, while Squamous cell Carcinoma (SCC), which originates in keratinocytes, is driven by TP53 mutations and epigenetic changes. In melanoma, mutations in genes like B-Raf proto-oncogene, serine/threonine kinase (BRAF), Neuroblastoma RAS Viral Oncogene Homolog (NRAS), Neurofibromin 1 (NF1), or proto-oncogene receptor tyrosine kinase (KIT) activate the MAPK pathway, leading to cellular proliferation and invasion. Traditional treatments, such as surgery, chemotherapy, and immunotherapies, face challenges like resistance, side effects, and don’t address widespread epigenetic alterations that activate oncogenes and silence tumor suppressors, emphasizing the need for targeted genetic therapies to inhibit skin cancer growth [Citation2]. Several gene expression inhibitors are being explored for cutaneous carcinomas, such as DNMT inhibitors (guadecitabine and decitabine, etc), which reverses abnormal DNA methylation to reactivate tumor suppressor genes, while EZH2 inhibitors (CPI-1205) block H3K27 trimethylation to prevent oncogenic gene silencing. HDAC inhibitors (entinostat, mocetinostat, and panobinostat), enhance histone acetylation to promote tumor suppressor expression and improve immune responses, and siRNA-based therapies (STP705 and c-Myc siRNA, etc) or antisense oligonucleotides targeting lncRNAs like MALAT1 and TINCR directly silence cancer-promoting genes and disrupt oncogenic pathways [Citation3]. Therefore, recent investigations focused on the regulation of gene expression and the development of their inhibitors as effective targeted therapeutic strategies for the treatment of cutaneous carcinoma.