Abstract
BackgroundDeregulation of EGFR signaling is common in non-small cell lung cancers (NSCLC) and this finding led to the development of tyrosine kinase inhibitors (TKIs) that are highly effective in a subset of NSCLC. Mutations of EGFR (mEGFR) and copy number gains (CNGs) of EGFR (gEGFR) and HER2 (gHER2) have been reported to predict for TKI response. Mutations in KRAS (mKRAS) are associated with primary resistance to TKIs.Methodology/Principal FindingsWe investigated the relationship between mutations, CNGs and response to TKIs in a large panel of NSCLC cell lines. Genes studied were EGFR, HER2, HER3 HER4, KRAS, BRAF and PIK3CA. Mutations were detected by sequencing, while CNGs were determined by quantitative PCR (qPCR), fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH). IC50 values for the TKIs gefitinib (Iressa) and erlotinib (Tarceva) were determined by MTS assay. For any of the seven genes tested, mutations (39/77, 50.6%), copy number gains (50/77, 64.9%) or either (65/77, 84.4%) were frequent in NSCLC lines. Mutations of EGFR (13%) and KRAS (24.7%) were frequent, while they were less frequent for the other genes. The three techniques for determining CNG were well correlated, and qPCR data were used for further analyses. CNGs were relatively frequent for EGFR and KRAS in adenocarcinomas. While mutations were largely mutually exclusive, CNGs were not. EGFR and KRAS mutant lines frequently demonstrated mutant allele specific imbalance i.e. the mutant form was usually in great excess compared to the wild type form. On a molar basis, sensitivity to gefitinib and erlotinib were highly correlated. Multivariate analyses led to the following results: 1. mEGFR and gEGFR and gHER2 were independent factors related to gefitinib sensitivity, in descending order of importance. 2. mKRAS was associated with increased in vitro resistance to gefitinib.Conclusions/SignificanceOur in vitro studies confirm and extend clinical observations and demonstrate the relative importance of both EGFR mutations and CNGs and HER2 CNGs in the sensitivity to TKIs.
Highlights
Lung cancer is the leading cause of all cancer deaths worldwide [1]
Since somatic mutations and copy number gains (CNGs) for Epidermal growth factor receptor (EGFR) pathway genes were rare in small cell lung cancer (SCLC), we limited our further studies to non-small cell lung cancers (NSCLC)
In contrast to SCLC, mutations or CNGs of the studied genes were frequent in NSCLC – 84.4% of NSCLC cell lines had a mutation, one or more CNGs or both
Summary
Lung cancer is characterized by the accumulation of multiple genetic and epigenetic alterations including somatic mutations and gene copy number gains or both which results in the activation of oncogenes or inactivation of tumor suppressor genes [3]. Epidermal growth factor receptor (EGFR) deregulation has been observed in multiple tumor types including non-small cell lung cancers (NSCLCs) [4]. EGFR over expression is often associated with adverse prognosis [6]. The receptor tyrosine kinase (RTK) super-family of cell surface receptors serves as mediators of cell signaling by extra-cellular growth factors. Deregulation of EGFR signaling is common in non-small cell lung cancers (NSCLC) and this finding led to the development of tyrosine kinase inhibitors (TKIs) that are highly effective in a subset of NSCLC. Mutations in KRAS (mKRAS) are associated with primary resistance to TKIs
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