Abstract
Abstract The HER2 gene ERBB2 is amplified and/ or overexpressed in up to 15% of all invasive breast cancers. These cancers are characterised by an aggressive phenotype and poor clinical outcome. HER2 positive tumours often display multiple high level amplifications of genes in addition to HER2. Although targeted therapies to HER2 have proven clinical benefit, a substantial number of patients have tumours that are either de novo resistant or acquire resistance over time to these agents. Reasons for this are still largely unknown. By using a high throughput siRNA screen we sought to determine whether genes recurrently amplified and overexpressed in HER2-amplified breast cancer mediate resistance to HER2-targeting agents. We profiled 45 HER2-amplified primary breast cancers and 13 HER2-amplified cell lines with high resolution microarray-based comparative genomic hybridisation (aCGH) and Illumina WG6 v2 arrays. Overlaying of aCGH and gene expression data led to the identification of 369 genes recurrently amplified and overexpressed when amplified. Lapatinib-resistant HER2-amplified breast cancer cell lines were treated with lapatinib, a HER2 small molecule inhibitor, and screened with an RNA interference (RNAi) library targeting these 369 genes and controls. This RNAi screen and subsequent validation screens identified eight genes that when silenced lead to a significant sensitization to lapatinib. The mechanisms of resistance conferred by the identified genes were further investigated and pointed to the involvement of NF-kappaB-signalling, Wnt-signalling and reactive oxygen species scavenging. Our results indicate that specific amplified and overexpressed genes found in HER2 positive breast cancers mediate resistance to anti-HER2 agents. These findings might be used to identify patients likely to be de novo resistant to lapatinib and provide new targets for combined targeted therapies to overcome resistance to anti-HER2 therapies. 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 4987. doi:10.1158/1538-7445.AM2011-4987
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