Abstract 708: Integrated analysis of drug resistance networks in breast cancer

Abstract

Targeted inhibition of HER2 tyrosine kinase receptor presents a promising strategy in the treatment of HER2-positive breast cancer patients. However, despite favorable response during the acute phase, majority of patients develop resistance to anti-HER2 drugs during the chronic phase of treatment. Here, we developed a cell culture model of chronic lapatinib (a dual inhibitor of EGFR and ERBB2 receptor tyrosine kinases) treatment by continuous passaging of HER2-overexpressing SKBR3 cells in increasing doses of lapatinib over a year. The resultant cell line, SKBR3-R, is almost 100-fold more resistant to lapatinib-induced growth inhibition when compared to the parental line. We have verified that this difference in lapatinib sensitivity is not due to altered expression or signaling at the level of HER2 or HER3 receptors in SKBR3-R cells. By integrating genome-wide gene expression profiling with our novel network-based genomic data analysis approach, we show that 1) cell toxicity mediated by acute lapatinib treatment in HER2-positive cells is associated with nutrient starvation and energy stress, and 2) chronic lapatinib treatment leads to the activation of compensatory cellular networks involved in the response to nutrient starvation, which confers resistance to lapatinib-induced cell death. Accordingly, while imposing a glucose starvation response phenotype on SKBR3 cells protects from lapatinib-mediated cell death, pharmacological inhibition of the nutrient starvation response in SKBR3-R cells reverses lapatinib resistance. In order to see if these networks play a role in breast cancer pathogenicity within clinical settings, we carried out a detailed network-based correlations of tumor gene expression profiles of breast cancer patients with their clinical data. Importantly, we found that the metabolic networks associated with lapatinib resistance are also associated with poor outcome within clinical settings. This study implicates nutrient deprivation response as a major factor in the acquired resistance of breast cancer cells to lapatinib, and suggests novel targets for combinatorial therapy of HER2-positive breast cancers. 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 708. doi:10.1158/1538-7445.AM2011-708