Abstract 4487: Targeting trastuzumab-resistant HER2+ breast cancer with a HER3-targeting nanoparticle

Abstract

Abstract HER2-positive breast cancers represent almost a quarter of invasive breast cancers and are indicative of poor patient survival. 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 new drugs that are effective against these HER2+ tumors that are non-responsive or have become resistant to these therapies. Recently, it has been shown that another member of the HER family, HER3, is commonly upregulated in these drug-resistant cancers. This observation led us to develop a novel drug delivery protein, called HerPBK10, that specifically targets another member of the HER receptor family, HER3. HerPBK10, once it has bound to the HER3 receptor, 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 due to the high levels of surface HER3 and would therefore provide an effective treatment for patients who have developed resistance to traditional therapies. First, we verified that cell surface levels of HER3 are elevated in trastuzumab-resistant cell lines compared to trastuzumab-sensitive cells. We then demonstrated, through competitive inhibition with free HER3 ligand, that HerPBK10 binds specifically to HER3 on multiple HER2+ cell lines. We assembled our targeted molecule, HerPBK10 with the chemotherapeutic doxorubicin. The resulting nanoparticle, called HerDox, was used to treat HER2+ breast cancer cell lines that were either inherently resistant to trastuzumab or had acquired resistance to trastuzumab. We demonstrated that HerDox caused significant cell death in both types of resistant cells. We also compared the effect of the HerDox nanoparticle to trastuzumab, pertuzumab, and the two drugs together and showed that it caused superior cell death in all three instances. In addition, we combined our nanoparticle with trastuzumab, and showed that together, they have an additive effect on cell death. These results indicate that our HER3 targeting nanoparticle, HerDox, efficiently targets and kills cancer cells that have become resistant to trastuzumab, and has the potential to be used either as a single drug or as part of a combinatorial therapy in eliminating drug-resistant HER2+ breast cancers. We are in the process of verifying these findings in vivo in order to demonstrate the potential of HerDox as a treatment for patients who have become non-responsive to traditional anti-HER2 therapies. Citation Format: Jessica Sims, Michael Taguaim, Chris Hanson, Xiaojiang Cui, Lali K. Medina-Kauwe. Targeting trastuzumab-resistant HER2+ breast cancer with a HER3-targeting nanoparticle. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4487. doi:10.1158/1538-7445.AM2014-4487