Abstract
BackgroundEfficacious application of HER2-targetting agents requires the identification of novel predictive biomarkers. Lapatinib, afatinib and neratinib are tyrosine kinase inhibitors (TKIs) of HER2 and EGFR growth factor receptors. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies.ResultsTreatment of HER2 TKI-sensitive SKBR3 and BT474 cell lines with lapatinib, afatinib and neratinib induced an increase in the expression of RB1CC1, ERBB3, FOXO3a and NR3C1. The response directly correlated with the degree of sensitivity. This expression pattern switched from up-regulated to down-regulated in the HER2 expressing, HER2-TKI insensitive cell line MDAMB453. Expression of the CCND1 gene demonstrated an inversely proportional response to drug exposure. A similar expression pattern was observed following the treatment with both neratinib and afatinib. These patterns were retained following exposure to traztuzumab and lapatinib plus capecitabine. In contrast, gefitinib, dasatinib and epirubicin treatment resulted in a completely different expression pattern change.ConclusionsIn these HER2-expressing cell line models, lapatinib, neratinib, afatinib and trastuzumab treatment generated a characteristic and specific gene expression response, proportionate to the sensitivity of the cell lines to the HER2 inhibitor.Characterisation of the induced changes in expression levels of these genes may therefore give a valuable, very early predictor of the likely extent and specificity of tumour HER2 inhibitor response in patients, potentially guiding more specific use of these agents.
Highlights
Overexpression of the epidermal growth factor (EGFR) family of proteins has been demonstrated to have significant negative therapeutic significance for breast cancer
CIA allowed us to identify commonality between the expression of the genes and the transcription factors (TF) that are predicted to target these genes. Using this gene panel of five (RB1CC1, FOXO3a, NR3C1, ERBB3 and CCND1), we examined the differential expression of these genes in response to pharmacologically relevant concentrations of neratinib, afatinib and traztuzumab to characterise if this panel informed on the sensitivity of the cell models to lapatinib alone or might be useful in predicting cellular response to other HER2-targetting therapies
Toxicological analysis of lapatinib, afatinib and neratinib in the cell line panel IC50 values were determined for lapatinib and were found to correlate with previously described values [2,17] for the 3 cell lines (BT474, SKBR3 and MDAMB453)
Summary
Overexpression of the epidermal growth factor (EGFR) family of proteins has been demonstrated to have significant negative therapeutic significance for breast cancer. This group of proteins is comprised of EGFR, HER2, HER3 and HER4 [1]. Non-targeted breast cancer treatment options may include one or more of chemotherapy, radiation, and surgery, while HER2 overexpressing breast cancers will typically involve trastuzumab-based therapy with newer agents such as lapatinib, providing a second line for treatment [2,5]. A panel of breast cancer cell lines was treated with these agents, trastuzumab, gefitinib and cytotoxic therapies and the expression pattern of a specific panel of genes using RT-PCR was investigated as a potential marker of early drug response to HER2-targeting therapies
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