Abstract
Abstract Purpose: While chemotherapy has improved lung cancer patient survival, relapse rates after neoadjuvant or adjuvant chemotherapy (minimal residual disease settings) are high. This could be due to cancer cells acquiring resistance to therapy or selective survival of pre-existing resistant cells. The molecular basis for primary or acquired resistance to standard platinum doublet chemotherapies are unknown and their elucidation is necessary for developing curative therapy that can be personalized for each patient. Methods: 3 complementary approaches were used to explore mechanisms underlying NSCLC resistance to platin-taxane chemotherapy: A) NSCLC lines were exposed in vitro to cycles of paclitaxel + carboplatin to mimic clinical treatment and resistance validated with cell viability and colony formation assays. Genome wide mRNA expression profiles of resistant and parental lines were compared using Illumina arrays and qRT-PCR. B) A large dataset of clinically and molecularly annotated NSCLC tumor specimens obtained after no chemotherapy or neoadjuvant platin-taxane chemotherapy were subjected to mRNA microarray analysis. C) Lung cancer xenografts were treated with chemotherapy in vivo in mice and profiled for mRNA expression. Biostatistical and bioinformatics approaches were used to identify genes that are differentially expressed in resistant cells in these three settings, and their function studied using over-expression or shRNA mediated knockdown. Results: NSCLC lines H1299 and H1355 were treated in vitro with paclitaxel + carboplatin and showed progressive increases in resistance to chemotherapy (after 5 to 15 cycles) ultimately achieving 30 (H1299) or 60 fold (H1355) differences compared to parental cells. In addition, multiple single cell clones also demonstrated chemotherapy resistance. Resistant NSCLC strains were also resistant to platin+docetaxel and platin+pemetrexed combinations. Expression profiles revealed upregulation of ABCB1/MDR1, down regulation of epithelial-specific genes suggesting EMT, differences in expression of epigenetic modulators as well as cancer testis family of GAGE genes and many of these genes had expression correlated with recurrence after neoadjuvant chemotherapy and with poor survival. Resistance was only partially reversed by verapamil indicating that it can be only partly explained by MDR mechanisms. Mechanistic studies of genes identified by these three approaches provide opportunities for overcoming chemotherapy resistance and developing novel therapies for NSCLC. Grant support: UT-Lung SPORE (5 P50 CA70907-11) and DoD PROSPECT (W81XWH-07-1-0306) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 821. doi:1538-7445.AM2012-821
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