Abstract A101: Treating trastuzumab-resistant HER2+ breast cancers with a HER3-targeted nanoparticle

Abstract

Abstract The human epidermal growth factor receptor subunit (HER2), or ErbB2, is receptor tyrosine kinase that is amplified in approximately 20-25% of invasive breast cancers. Anti-HER2 therapies such as trastuzumab (Herceptin®) have become important in the management of aggressive and metastatic breast cancer. Although many patients with HER2-positive breast cancer initially respond to anti-HER2 treatments, such as trastuzumab, a significant portion of them develop resistance to these therapies. Consequently, there is a great need to develop therapies that will treat these tumors once they become resistant. We have developed a unique drug delivery protein (HerPBK10) that specifically targets the cell surface receptor HER3, which has been shown to be elevated in trastuzumab-resistant HER2+ breast cancers. HerPBK10, once it has bound to the HER3 receptor subunit, triggers rapid endocytosis and endosomal penetration, enabling it to deliver a toxic payload to the cell, resulting in cell death. We hypothesized that cytotoxic drugs delivered by HerPBK10 would induce significant targeted cell death in trastuzumab-resistant Her2+ breast cancers and will provide an effective treatment for patients who have developed these resistant tumors. We have demonstrated that HerPBK10 binds specifically to HER3 in vitro and binds to the cell surface of three different breast cancer cell lines. Importantly, this binding can be competitively inhibited by free HER3 ligand, indicating that HerPBK10 binds specifically to HER3. We also examined whether cells that have become resistant to trastuzumab have altered levels of HER receptors on their surface when compared to parental, trastuzumab-responsive, cancer cells. We demonstrated in multiple trastuzumab-resistant cell lines that HER3 receptor levels are significantly increased. We then assembled HerPBK10 with a cytotoxic gallium corrole, which we have previously demonstrated to be toxic once taken up into a cell. The resulting nanoparticle, called HerGa, was used to treat three different aggressive breast cancer cell lines (one that is susceptible to trastuzumab treatment and two that have become resistant to trastuzumab) and demonstrated that HerGa caused cell death in all three cell lines, but at a greater level and at a lower dosage in the resistant cell lines. We also compared the effect of the HerGa nanoparticle to trastuzumab and showed that it caused greater overall cell death. Together, these results indicate that our HER3-targeting nanoparticle, HerGa, efficiently targets and kills cancer cells that have become resistant to trastuzumab, and warrants further in vivo testing to investigate its potential as a treatment for patients who have become non-responsive to traditional anti-HER2 therapies. Citation Format: Jessica D. Sims, Michael Taguaim, Chris Hanson, Xiaojiang Cui, Lali K. Medina-Kauwe. Treating trastuzumab-resistant HER2+ breast cancers with a HER3-targeted nanoparticle. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A101.