Dual inhibition of epidermal growth factor receptor and insulin‐like growth factor receptor I: Reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma

Abstract

Purpose-Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. The majority of the ~250,000 cases occurring annually in the United States are small, non-aggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and have increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve outcomes for patients with aggressive CSCC.Experimental Design-We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-IGF-IR antibody, A12, alone or in combination with an anti-EGF-R antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC. Results-Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of SCC cell lines in vitro.Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA) and microvessel density (MVD) as well as increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92% respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = 0.044 and p < 0.001 respectively).Conclusions-These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.

A New Bliss Independence Model to Analyze Drug Combination Data

“…11 Finally, various preclinical studies have shown improved activity when both IGF1R and EGFR are inhibited concomitantly. 12,13 Given that anti-IGF1R and anti-EGFR antibodies have shown toxicity clinically, it is important to study the combined effects of anti-IGF1R and anti-EGFR treatment quantitatively. Of particular interest is the hypothesis that subtoxic doses of each agent might yield efficacy comparable to that seen with toxic doses separately because of synergism when tested in combination.…”

Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

“…All receptors of the ErbB family activate and regulate diverse cellular processes, including proliferation, survival, adhesion, migration and differentiation (1). Ligand binding potentiates receptor interaction with either a homologous molecule (homodimerization), a different ErbB-family receptor, or another cell surface tyrosine kinase receptor (IGF-1R or c-Met) (heterodimerization) (2)(3)(4)(5). Dimer formation causes autophosphorylation of a tyrosine residue in the cytoplasmic domain and activates proteins triggering downstream events.…”

Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

“…EGFR tyrosine kinase inhibitors (TKI) can induce EGFR/IGF-1R heterodimerization and alter the interactions between IGF-1R and insulin receptor (INSR) substrate (IRS)-1 in cancer cells, activating downstream signaling and resulting in resistance to further TKI treatment (34)(35)(36). Conversely, coinhibition of both pathways results in synergistic antitumor effects in several preclinical cancer models (36)(37)(38)(39)(40)(41).…”