Abstract 2608: An intronic polymorphism determines TGF-alpha expression and is associated with cellular resistance to erlotinib

Abstract

Abstract An intronic polymorphism determines TGF-alpha expression and is associated with cellular resistance to erlotinib Wanqing Liu, Mark J Ratain Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA. Background Responsiveness to EGFR-targeting agents has been demonstrated in lung cancer patients bearing EGFR mutations. However, the detailed mechanism underlying both sensitivity and resistance to these agents has not been completely revealed. Expression of transforming growth factor alpha (TGFA), one of the major EGFR ligands, appears to affect the inhibition potency of EGFR inhibitors. The aim of this study is to identify the genetic variants that may affect TGFA expression and confer susceptibility to response to EGFR-targeting agents. Methods Genome-wide genotyping of 100K single nucleotide polymorphisms (SNPs) had been previously performed in the NCI-60 cancer cell panel. SNPs in the TGFA gene region were selected to perform correlations with TGFA mRNA expression measured by real-time PCR. Confirmation of the SNP genotypes was performed by both sequencing and restriction enzyme digestion. The SNP genotype was correlated with cytotoxicity data of erlotinib and other EGFR inhibitors. Results A total of 10 SNPs in the TGFA gene were genotyped on the 100K SNP Chip. The genotypes were confirmed. A SNP (rs3821262 C/T) in the second intron of TGFA was significantly associated with decreased TGFA gene expression and cellular resistance to both erlotinib (p=0.01) and other 11 EGFR inhibitors (p=0.05) tested in the NCI-60. Conclusion The SNP rs3821262 C/T may contribute to cellular resistance to EGFR inhibitors by modulating the gene expression. However, since this is a hypothesis-generating study and the association was not adjusted for multiple testing, the finding must be validated further in both preclinical and clinical settings, in particular combined with mechanistic studies. 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 2608.