Abstract 9: Imbalanced oncogenic signaling: Analogies between structurally distinct EGFR mutants of relevance to lung and brain cancers

Abstract

Abstract The epidermal growth factor receptor (EGFR) is expressed at elevated levels in a large fraction of brain, lung, breast, prostate, and head-and-neck cancers. Efforts to treat such cancers with EGFR-targeted antibodies and kinase inhibitors have had limited success, suggesting that the level of EGFR expression in a tumor is not generally a good predictor of response to drugs targeting EGFR. In some cases, however, response to EGFR-targeted agents correlates with the presence of certain EGFR mutations. For example, in non-small cell lung cancer (NSCLC), the small percentage of patients harboring kinase-activating mutations of EGFR (mostly small in-frame deletion and point mutations) respond unusually well to EGFR kinase inhibitors such as gefitinib and erlotinib. In glioblastoma multiforme (GBM), the presence of the EGFRvIII mutation (a distinct deletion mutation which also promotes elevated EGFR activity) is also associated with increased response to EGFR inhibitors, at least in cells expressing PTEN. Settings where the elevated activity of a particular kinase promotes cellular responsiveness to drugs targeting the kinase have been identified as examples of the phenomenon of “oncogene addiction.” One of the prevailing models for EGFR oncogene addiction holds that EGFR mutations simultaneously lead to the increased activities of pro-survival and pro-apoptotic signaling pathways, with the latter persisting longer in response to EGFR inhibition and ultimately prevailing in determining cellular phenotypes. Here, we offer an alternative explanation for at least part of the altered cellular sensitivity to EGFR inhibition observed in the context of EGFR mutation in NSCLC and GBM. Specifically, we demonstrate that downstream of these structurally distinct EGFR mutants an important pathway involving the activation of ERK via the protein tyrosine phosphatase SHP2 is functionally impaired, and that this perturbs cellular responsiveness to gefitinib. Based upon immunoprecipitation, immunofluorescence, activity, and receptor trafficking studies, this mechanism appears to involve the sequestration of biochemically active SHP2 with endocytosis-impaired EGFR mutants at the plasma membrane in a manner which prevents the participation of SHP2 in the complete activation of ERK. Thus, our findings demonstrate that distinct EGFR-activating mutations may result in qualitatively similar perturbations to downstream signaling leading to the surprising impairment of receptor-mediated ERK activation. Given that elevated expression of these EGFR mutants generally promotes cellular response to EGFR inhibitors, this work identifies SHP2 and ERK as potentially critical nodes in the signaling network downstream of EGFR for co-inhibition in settings where EGFR inhibitors are not effective as single agents. 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 9. doi:1538-7445.AM2012-9