Abstract
Abstract Background: Low BRCA1 mRNA expression significantly prolongs progression-free survival (PFS) to erlotinib in EGFR-mutant NSCLC patients (p). In order to explore other genes potentially involved in erlotinib resistance, we used NanoString, an integrated digital technology, to examine expression levels of 48 genes in a single reaction. Several genes involved in homologous recombination repair were included in the 48-gene assessment, including the E3 ubiquitin ligases RNF8, RNF168 and RAP80. Methods: CodeSets (Reporter and Capture probe sets) for 48 genes were custom-designed by NanoString Technologies. 100ng of total RNA for each sample was mixed with the reagents and hybridized at 65° overnight. Samples were processed and analyzed with the nCounter Prep Station (NanoString Technologies). Data analysis was performed adjusting the expression values according to positive control values and normalizing the data according to housekeeping genes. Results: In 43 EGFR-mutant NSCLC p treated with erlotinib, response rate was 67.6%, PFS was 16 months (m), median survival (MS) was 29 m. Three genes were significantly associated with PFS: PIAS1, DBC1 and AEG-1. Median PFS was not reached in p with low levels of AEG-1, while it was 18 m for p with intermediate levels and 5 m for p with high levels (P=0.002). In the multivariate analysis, the hazard ratio for high levels of AEG-1 was 14 (P<0.001). Conclusions: AEG-1 activates the NF-κB and PI3K/Akt pathways, induces the transcription factor LSF, which upregulates TS, ALDH3A1 and Met, conferring resistance to several cytotoxic drugs. AEG-1 mRNA expression predicts outcome to erlotinib-treated EGFR-mutant NSCLC p and could have important implications for the optimal management 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 4110. doi:10.1158/1538-7445.AM2011-4110
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