Abstract 232: Targeting HER3 mRNA by a locked nucleic antisense molecule enhances the antitumor activity of gefitinib in vivo

Abstract

Abstract Background: The HER family consists of four tyrosine kinase receptors designated as EGFR, HER2, HER3 and HER4. HER3 is a unique member that plays a critical role in tumor growth since it 1) can heterodimerize with EGFR or HER2 and is the main link to the downstream PI3K/Akt signaling axis, 2) can mediate resistance to HER1/2-targeted therapeutics, and 3) unlike EGFR or HER2, is not typically overexpressed but still hyperphosphorylated in a variety of tumors. Resistance to the EGFR-tyrosine kinase inhibitors, such as gefitinib, can be associated with EGFR mutations and/or activation of HER3 ultimately leading to activation of the PI3K/AKT axis. We have used an RNA antagonist of HER3, designated EZN-3920, to explore the ability of this compound to inhibit tumor growth and overcome resistance to HER1/2 therapeutics. Methods: Tissue culture cells were treated with EZN-3920, a locked nucleic acid (LNA)-based oligonucleotide complementary to HER3. Compound was either added to tissue culture media (i.e. no transfection) in vitro or prepared in saline and given IV in vivo. Endpoints were measured by qRT-PCR, MTT, Western Blot analysis, Immunohistochemistry, and tumor size. Results: EZN-3920 down modulated HER3 mRNA, protein expression, PI3K/AKT signaling, and inhibited tumor cell proliferation. In vivo, systemic administration of EZN-3920, prepared in saline, resulted in specific down- modulation of HER3 mRNA and protein expression, as well as blockade in PI3K/AKT signaling pathways in NSCLC HCC827 associated with tumor growth inhibition. Similar results were also shown in tumor derived from BT-474-M1 breast carcinoma xenograft models. Interestingly, in the HCC827 tumor model, EZN-3920 at 30 mg/kg (biweekly for 4 weeks, i.v.) and gefitinib at 15 mg/kg (5 times a week for two weeks) completely shrank established tumors while either treatment alone only delayed tumor growth by 40-60%. Conclusions: The studies suggest that down regulation of HER3 by antisense molecule EZN-3920 inhibits human tumor growth in mice. Beyond this, antitumor effects of gefitinib can be enhanced by HER3 down modulation in gefitinib-sensitive tumors. On-going studies will determine if tumors that are resistant to HER1/2 therapeutics will either have enhanced sensitivity to EZN-3920 and/or the compound can restore sensitivity to such agents. 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 232. doi:10.1158/1538-7445.AM2011-232