Abstract 4114: IGF-1R and EGFR expression and IGF-1R mutational status in non-small cell lung cancer (NSCLC)

Abstract

Abstract Background: Lung cancer is the commonest cause of cancer related deaths worldwide and has a very poor prognosis Recent evidence indicates that epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor 1 (IGF-1R) interact in the pathogenesis of malignant epithelial tumours including lung cancer. IGF-1R suppresses apoptosis primarily through the phosphoinositide 3-kinase (PI3K) pathway. Currently, several different approaches are being investigated for targeting the IGF-1R. EGFR targeted therapies are now established in the first and second line treatment of NSCLC. Somatic mutations in the tyrosine kinase domain of a receptor can alter its activity and impact on the ability of an inhibitor to bind efficiently. To date there is limited knowledge of mutations in the IGF-1R tyrosine kinase domain. The aims of this study are (i)to examine EGFR and IGF-1R expression and (ii)to screen for mutations in the tyrosine kinase domain of the IGF-1R in a cohort of 184 NSCLC patients and to correlate the results to patient survival/pathological data. Methods: The expression of IGF-1R and EGFR were examined in a panel of cell lines and 20 resected normal/tumour matched NSCLC patient tissues(10 Adenocarcinomas (ADC) and 10 Squamous (SCC)) using Western Blot analysis. IGF-1R and EGFR expression was evaluated in 184 patients using immunohistochemistry analysis and the results were scored by a pathologist. The DNA from the same cohort of patients is being examined for mutations in the tyrosine kinase domain of the IGF1R using sequencing analysis. Results: A panel of NSCLC cell lines showed differences in IGF1R expression. In the fresh frozen resected NSCLC tumours IGF-1R and EGFR were overexpressed relative to matched normal tissues. SCC had higher levels of expression than ADC. IGF-1R 3+/2+ expression was observed in 53.8% of NSCLC with SCC having higher expression than non-SCC(62.6% versus 37.3%,p=0.0004).EGFR 3+ expression was detected in 51% of NSCLC and SCC had higher EGFR expression than non-SCC (57.4% versus 42.5%,p=0.028).A significant association was shown between IGF-1R 3+/2+ and EGFR 3+ protein expression(p <0.005). Patients with EGFR and IGF-1R overexpression had a poorer overall survival(p=0.04). To date 100 patients have been screened for mutations and we have detected a polymorphism(3129A >G) in exon 16 of IGF1R in a significantly higher proportion of NSCLC patients and than in an age/race/gender-matched disease-free control population. Conclusions: Our findings indicate a close inter-relationship between IGFR and EGFR. EGFR and IGF-1R expression alone are not independent prognostic markers in NSCLC. In contrast co-expression correlates with a poor survival. This subset of patients may benefit from treatments co-targeting IGF-1R and EGFR. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4114.