Abstract 163: mRNA and miRNA profiling of platinum-resistant non-small cell lung cancer cell clones identifies potential targets involved in DNA metabolism and DNA replication

Non small cell lung cancer (NSCLC) constitutes the majority of lung cancer diagnoses and platinum-based chemotherapy regimen is the standard treatment. Unfortunately, a large proportion do not respond or relapse on such treatment regimens for yet only partly revealed mechanisms. We profiled residual clones of NSCLC cells after treatment with cisplatin. The mRNA and miRNA pattern was compared between untreated and cisplatin-resistant NSCLC clones using Affymetrix gene and miRNA expression arrays, respectively. We found that around 1100 genes were up regulated (at least two fold) and about 1200 genes were down regulated (at least two fold) in the cisplatin-resistant clones compared with untreated NSCLCs. We then used the Gene Set Enrichment Analysis (GSEA) to find the over- and underrepresented gene sets in large datasets like, Gene Trail and Gene Ontology. We found that cisplatin-refractory NSCLCs showed increased expression of genes involved in different cellular mechanisms including DNA metabolic processes, DNA replication and DNA-dependent DNA replication initiation for example, XRCC2, FANCI, FANCD2, RRM1, MRE11A, BLM, RRM2 and TOP2A which were validated on RNA, protein and functional level for their role in cisplatin sensitivity of NSCLC. We also found a few miRNAs that were up regulated in cisplatin refractory NSCLC by a least 1.3-fold e.g. miRNA-25 star and miRNA-1290. Interestingly, only 14 miRNAs were down regulated (by at least 1.3 fold) in the surviving cisplatin refractory NSCLC cells. Among these miRNAs were (miR-29b, miR-210, miR-486-3p, miR-324-5p, miR-572, miR-30a, e, miR-424, miR-449a, b, miR-301a, miR-153, miR-150 star and miR-34c-5p). We then looked for the predicted targets of these miRNAs using Target scan and microcosm and we found a large list of genes to be potential targets of the miRNAs among them are genes involved in apoptosis, cell cycle regulation, Wnt signaling pathway and other cellular processes (ex. VDAC, SMAD2, RAN, etc.). Correlation analysis between miRNA gene targets and gene expression data is ongoing with the aim to identify and validate putative targets on RNA, protein and functional level. In conclusion, our data show that cisplatin refractory NSCLC tumors have dysregulated mRNAs and miRNAs. Among the dysregulated genes, are certain genes involved in DNA metabolism, DNA replication and DNA-dependent DNA replication initiation which may be novel targets for improved platinum-based therapy response of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 163. doi:10.1158/1538-7445.AM2011-163