Abstract
Dysregulation of the epidermal growth factor receptor family (EGFR, HER2, HER3, HER4) by mutation and/or overexpression plays an important role in tumorigenesis, and targeted agents directed against two members of the HER/ErbB family, epidermal growth factor receptor (EGFR/HER1), and HER2/ErbB2, are used in the treatment of cancer. Extensive crosstalk seen among these receptors implies that blocking signaling of more than one receptor may be more effective in inhibiting tumor growth and circumventing resistance mechanisms than targeting individual receptors. In particular, HER3 is considered a key mediator of resistance to many targeted agents. We generated a “two-in-one” antibody, MEHD7945A, that binds to EGFR and HER3 with high affinity, inhibits receptor function and is more broadly efficacious in various tumor types when compared to monospecific anti-EGFR or anti-HER3 antibodies. Given the ability of HER3 to potently activate the PI3K survival pathway, we investigated if antagonizing ligand-dependent HER signaling with MEHD7945A in the presence of chemotherapy augments cytotoxicity. We calculated combination index values the effects of combining MEHD7945A with commonly used chemotherapeutic agents in NSCLC and colorectal cell lines in vitro and in vivo. The NSCLC lines NCI-H292, NCI-H1666, NCI-H358 and HCC827 were treated with MEHD7945A plus gemcitabine over a wide range of drug concentrations. Cell proliferation data were analyzed using CalcuSyn software and all combination index values were <1, demonstrating that the combination of MEHD7945A and gemcitabine inhibited proliferation synergistically in these cells. To further explore the enhanced cytotoxic effect we evaluated the combination of MEHD7945A and gemcitabine, versus each single agent, in the NCI-H1975 NSCLC xenograft model, and observed enhanced tumor regression. Similar results were observed when MEHD7945A was combined with a range of chemotherapeutic agents, including pemetrexed, docetaxel and irinotecan in H1975, H441 or SW948 xenograft models. In summary, these in vitro and in vivo results demonstrate that MEHD7945A potentiates various cytotoxic agents in a variety of tumor types.
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 1212. doi:1538-7445.AM2012-1212
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
