Abstract
Abstract Objective of the study: Trastuzumab is a highly successful example of rationally designed ERBB2-targeted therapy. However, about half of patients with ERBB2-overexpressing breast cancer do not respond to trastuzumab-based therapies due to various resistance mechanisms. Clinically applicable regimens for overcoming trastuzumab resistance of different mechanisms are not yet available. The objective of the study is to find a common key node of multiple trastuzumab resistance mechanisms and design a clinical applicable strategy to target this common node to more effectively overcome trastuzumab resistance. Methodology: First, we evaluated Src activity in multiple acquired and de novo trastuzumab-resistant cell lines models. Cells with modulated Src activity were examined for trastuzumab resistance in vitro and in an orthotopic xenograft model. Moreover, tumors from patients receiving trastuzumab therapy were also analyzed retrospectively for clinical correlation of Src activity with trastuzumab response. Src activated trastuzumab-resistant cells were further treated with Src inhibitor (saracatinib), trastuzumab, or a combination of both in vitro and in vivo. Results: We demonstrate that the non-receptor tyrosine kinase Src serves as a critical modulator of trastuzumab response and a common node downstream of multiple trastuzumab resistance pathways. Src is activated in both acquired and de novo trastuzumab-resistant cells. Increased Src activation conferred significant trastuzumab resistance (P = 0.011) in breast cancer cells and correlated with trastuzumab resistance in patients. Targeting the common node Src in combination with trastuzumab universally sensitized multiple lines of trastuzumab-resistant cells to trastuzumab and eliminated trastuzumab-resistant tumors in vivo. Targeting Src, a critical convergence point of divergent trastuzumab resistance mechanisms, represents a highly effective and clinically convenient strategy to overcome trastuzumab resistance. 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 LB-379. doi:10.1158/1538-7445.AM2011-LB-379
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