The Promise of Genomics and the Development of Targeted Therapies for Cutaneous Squamous Cell Carcinoma

Abstract

Targeted therapies for melanoma and basal cell carcinoma have evolved from deciphering the molecular mechanisms involved in their tumorigenesis. Mutations in BRAF have led to clinical use of BRAF-inhibitors in advanced melanoma, and mutations in Hedgehog signaling to smoothened inhibitors in basal cell carcinoma. The development of tumor resistance to these treatments is leading to many new drug development initiatives and the exploration of multiple signalling pathways. Cutaneous squamous cell carcinoma continues to rise steeply in incidence with very limited therapeutic options for locally advanced or metastatic disease. New genetic technologies find significant levels of mutation in Notch gene family as well as other already recognized gene mutations, such as TP53. The mutational burden in cutaneous squamous cell carcinoma is massive, challenging the identification of driver genes and inhibiting translation from genomics to the clinic. Clinical experience with targeted therapies, such as epidermal growth factor receptor inhibitors, or immune modulatory drugs suggests that these agents may be of benefit to patients, while a more complete understanding of the mechanisms behind squamous cell carcinogenesis awaits further progress.

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Therefore, current treatments of SCC are directed toward upstream regulators and downstream effectors of the Notch pathway, which has been extensively studied and well reviewed for CSCC 97. New understanding of Notch signaling may lead to therapeutic development for less‐characterized SCC types.…”

Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma

“…Genetic and genomic studies along the last decade have provided clues on the mutational landscape of cSCC [7][8][9]. However, the existence of a very high burden of mutation in cSCC, greater than in other solid tumours, makes difficult to identify the precise genetic events and number of mutations required for squamous cell carcinogenesis [10]. Alterations in the p53 gene are the most common genetic abnormalities found in AK and invasive cSCC, and deregulation of p53 pathway appears to be an early event in carcinogenesis of cSCC [11,12].…”

Azathioprine: friend or foe?

“…Advances in genomics technologies provide new opportunities to understand the mechanisms of skin carcinogenesis, with the promise of developing novel targeted therapies and personalized cancer treatments . Recent expansion of national registration of skin cancer in the U.K. has demonstrated the huge number and increasing frequency of keratinocyte cancers (KC), highlighting the importance of better understanding their molecular pathogenesis in order to aid diagnostic, treatment and prevention strategies.…”

“…Mutations in TP53 have been extensively reported in both animal models and human tumours. Further publications have also highlighted other potential drivers such as CARD11 mutations and loss of function mutations in transforming growth factor beta receptors TGFBR1 and TGFBR2 …”