Abstract P5-08-08: A human epidermal growth factor receptor 3 (HER3)-binding nanoparticle targets and kills Herceptin®-resistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer
Authors: Sims JD , Taguaim M , Hanson C , Cui X , Medina-Kauwe LK 
Published: August 2014

Abstract
The human epidermal growth factor receptor subunit (HER2), or ErbB2, is a 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 Herceptin, 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. Recently it has been shown that another member of the HER family, HER3, is commonly upregulated in these tumors. This led us to develop a unique drug delivery protein (HerPBK10) that specifically targets the cell surface receptor, 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 Herceptin-resistant, HER2+ breast cancers and would provide an effective treatment for patients whose tumors have become resistant to traditional therapies. We have demonstrated that HerPBK10 binds to the cell surface of three different HER2+ breast cancer cell lines and that this binding can be competitively inhibited by free HER3 ligand, indicating that HerPBK10 binds specifically to HER3. Next, we showed in multiple Herceptin-resistant cell lines that HER3 receptor levels are significantly increased in drug-resistant cells, confirming the results of other researchers. We then assembled our targeted molecule, HerPBK10 with the chemotherapeutic doxorubicin. The resulting nanoparticle, called HerDox, was used to treat two different HER2+ breast cancer cell lines that are susceptible to Herceptin treatment and two that had acquired Herceptin resistance. We demonstrated that HerDox caused cell death in all cell lines, but at a greater level and at a lower dosage in the drug-resistant lines. We also compared the effect of the HerDox nanoparticle to Herceptin and showed that it caused greater overall cell death. In addition, we combined our nanoparticle with Herceptin, and showed that together, they induced even greater cell death. These results indicate that our HER3 targeting nanoparticle, HerDox, efficiently targets and kills cancer cells that have become resistant to Herceptin, 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 Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-08-08.