Molecularly targeted therapeutics hold promise of revolutionizing treatments of advanced malignancies. However, a large number of patients do not respond to these treatments. Here, we take a systems biology approach to understand the molecular mechanisms that prevent breast cancer (BC) cells from responding to lapatinib, a dual kinase inhibitor that targets human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR). To this end, we analysed temporal gene expression profiles of four BC cell lines, two of which respond and the remaining two do not respond to lapatinib. For this analysis, we developed a Gaussian process based algorithm which can accurately find differentially expressed genes by analysing time course gene expression profiles at a fraction of the computational cost of other state-of-the-art algorithms. Our analysis identified 519 potential genes which are characteristic of lapatinib non-responsiveness in the tested cell lines. Data from the Genomics of Drug Sensitivity in Cancer (GDSC) database suggested that the basal expressions 120 of the above genes correlate with the response of BC cells to HER2 and/or EGFR targeted therapies. We selected 27 genes from the larger panel of 519 genes for experimental verification and 16 of these were successfully validated. Further bioinformatics analysis identified vitamin D receptor (VDR) as a potential target of interest for lapatinib non-responsive BC cells. Experimentally, calcitriol, a commonly used reagent for VDR targeted therapy, in combination with lapatinib additively inhibited proliferation in two HER2 positive cell lines, lapatinib insensitive MDA-MB-453 and lapatinib resistant HCC 1954-L cells.
Dublin City University ->