The epidermal growth factor receptor in squamous cell carcinoma: An emerging drug target

Abstract

Squamous cell carcinoma (SCC) of the skin is an increasingly common diagnosis worldwide. Together with precursor lesions, SCC carry a significant morbidity, particularly in regions with high solar UV radiation levels. Advanced lesions are locally or sometimes widely metastatic and may be resistant to treatment. Drugs targeting the epidermal growth factor receptor (EGFR) are currently the only significant non-surgical option for advanced SCC beyond radiotherapy and conventional chemotherapy. The role of the EGFR in skin cancer is described and the outcomes of targeted anti-EGFR therapy published to date are summarised. The future of anti-EGFR targeted therapies in the treatment of skin cancer is discussed. Targeted molecular therapies are becoming increasingly widespread and an understanding of the evidence for their use as well as their side effect profile is important in order to offer patients informed and current advice.

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…Data supports a strong correlation between solar ultraviolet radiation (UVR) and mutational burden in the p53 gene with up to 90% of squamous cell carcinomas exhibiting p53 mutations. (131,133,134) It is thought that UV radiation has direct effects at the TP53 locus with mutations affecting cell cycle regulation and allowing clonal expansion to occur. (134,135) Members of the mitogen activated protein kinase (MAPK) family are also thought to play a significant role in in cSCC.…”

“…EGFR is known to be constitutively activated in a subset of invasive cSCC and is an important emerging drug target. (133) Homo-or heterodimerisation induced by ligand binding or directly by UVR results in auto phosphorylation of the intracellular tyrosine kinase, activating downstream signalling and promoting cell proliferation, migration, survival and suppression of differentiation. (135) On the other hand, mutations in the EGFR are not known to play an important role in the carcinogenesis or progression of cSCC, as they are at some other sites.…”

High-risk Cutaneous Squamous Cell Carcinoma

“…85 Targeted therapies and forms of immunotherapy utilize the overexpression of epidermal growth factor receptor (EGFR) in the setting of cSCC to disrupt cell proliferation. [86][87][88] These novel treatments, which include monoclonal antibodies, such as cetuximab, can offer an overall disease control rate of 69%, as seen in a phase II trial using cetuximab in the setting of metastatic cSCC. 88 A further stage III randomized trial adding cetuximab to cisplatin significantly improved treatment response when compared with placebo (26.3 vs 9.8%; p=0.29).…”

“…[86][87][88] These novel treatments, which include monoclonal antibodies, such as cetuximab, can offer an overall disease control rate of 69%, as seen in a phase II trial using cetuximab in the setting of metastatic cSCC. 88 A further stage III randomized trial adding cetuximab to cisplatin significantly improved treatment response when compared with placebo (26.3 vs 9.8%; p=0.29). 89 The promising human immunoglobulin G-2 monoclonal antibody against EGFR, panitumumab, demonstrated a 31% response rate in a phase II study of 16 patients with recurrent or metastatic SCC.…”

Squamous Cell Carcinoma

“…The future of anti-EGFR-targeted therapies in the treatment of skin cancer is discussed. Other strategies to potentiate the antitumor activity of cytotoxic agents such as docetaxel or cisplatin are also discussed (Gaffney et al 2013 ). Targeted molecular therapies are becoming increasingly widespread and an understanding of the evidence for their use as well as their side effect profi le is important in order to offer patients informed and current advice.…”