Abstract 2417: A new mouse model for epithelial ear neoplasms based upon expression of mutant EGFRL858R/T790M

Abstract

Abstract Epithelial neoplasms of the ear are rare and difficult to detect before the development of audiovestibular or facial nerve dysfunction. Complete resection is often difficult because of location and the late stage at diagnosis, so effective chemotherapy is required. No preclinical models exist for these tumors. During the generation of mice using CC10 or surfactant protein C (SP-C) promoters to drive expression of mutant EGFR (EGFRL858R/T790M) in lung tissues, we observed that no SP-C mice developed lung tumors, but approximately 30% of them developed head tilt and a circular gait by 25 wk. MRI scans showed bilateral ear tumors located in the tympanic cavity that partially invaded into temporal bone, which suggested the presence of middle ear tumors or endolymphatic sac tumors (ELSTs). Histology of the ear tumors showed well-differentiated adenocarcinomas with multiple papillary and microcystic structures. Immunohistochemical (IHC) analysis showed that the mutant EGFR was active and selectively expressed in the tumors, and that downstream components of EGFR signaling such as Akt, mTOR and ERK were activated. SP-C expression was also detected, suggesting that surfactant proteins are expressed in ear epithelium at specific times during tumor development. To determine if these tumors were addicted to EGFR signaling, EGFR-based therapies were tested in symptomatic mice. Consistent with the T790M mutation in EGFR conferring resistance to reversible EGFR tyrosine kinase inhibitors (TKI), erlotinib was ineffective. In contrast, the combination of an irreversible EGFR TKI (BIBW-2992) with an antibody against EGFR (cetuximab), or a chemically optimized analogue of BIBW-2992 (WZ4002) used alone, was highly effective. All mice treated with the combination or WZ4002 alone had normalization of gait and complete responses by MRI, suggesting that these tumors are dependent upon mutant EGFR. To assess the possible clinical relevance of this mouse model, 2 human middle ear adenocarcinomas and a human ELST were stained for active EGFR using IHC. 3/3 displayed increased EGFR activation. These studies describe a new mouse model for human epithelial ear tumors based on EGFR activation, and raise the possibility that EGFR-based therapies might have clinical efficacy in these rare neoplasms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2417. doi:10.1158/1538-7445.AM2011-2417