Abstract
Abstract The epidermal growth factor receptor (EGFR) family consists of four members including HER1 (EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Collectively this family of receptor tyrosine kinases (RTKs) play critical roles in the etiology of several human cancers as well as a role in resistance to radiation therapy. In 2006, a study in head and neck squamous cell carcinoma (HNSCC) indicated that using the anti-EGFR antibody cetuximab in combination with radiation resulted in a 10% advantage of 3-year overall survival rate when compared to radiotherapy alone. This study highlighted the therapeutic utility of RTK blockade in combination with radiation. Studies investigating the role of HER3 in radiation response are limited. In the present study, we investigated whether or not HER3 blockade could enhance radiation therapy using the HER3 antibody U3-1287/AMG888. We screened a battery of cell lines from lung, HNSCC and colorectal tumor lines for HER3 expression. The results indicated that all 15 cell lines tested showed expression of HER3. In addition, U3-1287/AMG888 was able to block basal HER3 activity and radiation induced HER3 activation. Further, proliferation assays, using U3-1287/AMG888, indicated that HER3 blockade could block proliferation in SCC6, SCC1483, H226 cell lines, highlighting the importance of HER3 in these tumor cells. Clonogenic assays showed that U3-1287/AMG888 could sensitize these lines to radiation. Furthermore, γ-H2AX analyses, detected by immunofluorescence, lead to a statistically significant increase in apoptotic cells. Cell cycle analysis, 24 and 48 hours after U3-1287/AMG888 and radiation treatments resulted in a significant G1 and G2 cell cycle arrest. Annexin-V binding assays showed a significant increase in apoptosis in the U3-1287/AMG888 plus radiation group as compared to either agent alone. To determine if HER3 blockade using U3-1287/AMG888 could enhance radiation therapy in vivo we performed tumor growth delay experiments using SCC6, SCC1483 and H226 xenografts in nude mice. Mice were inoculated and treated with 1) IgG, 2) U3-1287/AMG888, 3) radiation or 4) the combination. The results of these experiments indicated that the combination of U3-1287/AMG888 and radiation had a strong impact on tumor growth in studies using single dose or fractionated dosing. Tumor analysis indicated that radiation treatment activated HER3 in vivo and U3-1287/AMG888 could abrogate this activation. Collectively our findings in vitro and in vivo suggest that U3-1287/AMG888 in combination with radiation has an impact on cell and tumor growth by impacting cell cycle progression, increasing apoptosis and increasing DNA damage. These findings suggest that HER3 may play a critical role in response to radiation therapy and blocking its activity may be of strong therapeutic benefit in human tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5726. doi:1538-7445.AM2012-5726
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