Molecular targeted therapies for cutaneous squamous cell carcinoma: recent developments and clinical implications

Abstract

Cutaneous Squamous Cell Carcinoma (cSCC) is a common and potentially fatal type of skin cancer that poses a significant threat to public health and has a high prevalence rate. Exposure to ultraviolet radiation on the skin surface increases the risk of cSCC, especially in those with genetic syndromes like xerodermapigmentosum and epidermolysis bullosa. Therefore, understanding the molecular pathogenesis of cSCC is critical for developing personalized treatment approaches that are effective in cSCC. This article provides a comprehensive overview of current knowledge of cSCC pathogenesis, emphasizing dysregulated signaling pathways and the significance of molecular profiling. Several limitations and challenges associated with conventional therapies, however, are identified, stressing the need for novel therapeutic strategies. The article further discusses molecular targets and therapeutic approaches, i.e., epidermal growth factor receptor inhibitors, hedgehog pathway inhibitors, and PI3K/AKT/mTOR pathway inhibitors, as well as emerging molecular targets and therapeutic agents. The manuscript explores resistance mechanisms to molecularly targeted therapies and proposes methods to overcome them, including combination strategies, rational design, and optimization. The clinical implications and patient outcomes of molecular-targeted treatments are assessed, including response rates and survival outcomes. The management of adverse events and toxicities in molecular-targeted therapies is crucial and requires careful monitoring and control. The paper further discusses future directions for therapeutic advancement and research in this area, as well as the difficulties and constraints associated with conventional therapies.

Keywords: clinical implications; clinical trials; combination strategies; patient; skin cancer.

Figure 1. Overview on the causes, diagnosis, signs, and symptoms and the treatment approach used for cSCC. Figure created with BioRender.

Figure 2. Various signaling pathways involved in the pathogenesis and therapeutic strategies of cSCC. (A) RAS signaling pathway, there are two key pathways involved: the MAP kinase pathway and the PI3K pathway. These regulate the cell cycle, death of cells, cell metabolism, and the production of proteins. Green arrows represent activation, whereas red lines represent inhibition. (B) The route of Wnt signaling. Catenin, a critical component of the Wnt pathway, has two roles. It functions as a transcriptional activator in the nucleus, regulating development of cell, as well as a component of cell adhesion junctions. (C) The Hedgehog route. The reaction of hedgehog ligands with the receptors in the membrane. (D) Notch Pathway. Cell-to-cell contact is required for Notch signaling. Notch ligands on a neighboring cell bind to Notch, leading it to undergo degradation by two proteases. This results in the release of the Notch cytoplasmic domain, which then migrates to the nucleus to communicate with transcription factors, reproduced with permission from reference (Juliano, 2020).

Figure 3. Current medicinal system and its lacunae in the treatment of various diseases in comparison with personalized medicine in Ayurveda and its efficacy for individual patients, reproduced with permission from Sharma and Prajapati (2020), Copyright 2020, Springer.

Figure 4. Personalized therapy using liquid biopsy, tumor-derived organoids, and tumor-derived xenografts based on genomic assessment of the original tumor or metastases, reproduced with permission from Gambardella et al. (2020)