Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have been used to treat non-small cell lung cancer (NSCLC), and a better response and prolonged survival have been observed in patients who harbor EGFR mutations [1,2]. However, despite a dramatic response, most NSCLC patients experience drug resistance and tumor progression. Two major resistance mechanisms of a secondary point mutation of T790M and MET gene amplification have been reported [3,4]. However, the resistance mechanism remains largely unknown. Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that plays a crucial role in cancer cell proliferation, inhibition of apoptosis, angiogenesis, and anchorage-independent growth via the phosphatidylinositol 3-kinase-AKT and RAS/RAF/mitogen activated protein kinase signaling pathways [5,6]. In addition, both in vitro and in vivo studies have revealed extensive crosstalk between EGFR and IGF1R signaling on multiple levels [7-10]. These data indicate that IGF1R can lead to acquired resistance against EGFR-targeted drugs, and targeting both receptors could provide better efficacy in cancer treatment by overcoming drug resistance [11,12]. Despite extensive research to clarify the clinical significance of IGF1R in NSCLC, the characteristics and implicated prognostic value remain controversial. Cappuzzo et al. [10] have suggested that patients who have high IGF1R expression and are receiving gefitinib therapy might have improved outcomes compared with those with lower expression. In addition, Kikuchi et al. [13] reported that low IGF1R expression was associated with poor prognosis in lung adenocarcinomas (ADCs). In contrast, Tsuta et al. [14] revealed that, in surgically treated patients, IGF1R protein expression, copy number and IGF1R bright-field in-situ hybridization positivity did not correlate with overall survival. These discrepancies might partly be attributable to the heterogeneity of the study groups including ethnicity, histologic subtypes, and molecular subtypes. To address these differences, we investigated the expression and clinical significance of IGF1R expression in histologically and genotypically specified subgroups of NSCLC.