Role of ERRFI1 in mutant EGFR-driven lung tumorigenesis

Division Of Basic Sciences - Nci

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Abstract

We identified MIG6 (gene symbol ERRFI1) as a phosphorylation target of mutant EGFRs in our mass spectrometry-based experiments. MIG6, also known as ERBB receptor feedback inhibitor 1 (ERRFI1) and receptor-associated late transducer (RALT), is a scaffolding adaptor protein whose expression is rapidly induced by a variety of growth factors (including EGF) and by hormones and other stressors. MIG6 negatively regulates EGFR, ERBB2, and several other receptor tyrosine kinases and their signaling pathways. We hypothesized that loss of MIG6 may cooperate with mutant EGFR to induce lung tumorigenesis. To test this hypothesis we crossed doxycycline inducible mutant EGFR transgenic mice with Mig6 null mice. Upon doxycycline induction of mutant EGFRs that are expressed in type II epithelial cells, lung tumorigenesis is indeed accelerated upon loss of Mig6 expression. We are currently performing further biochemical assays to identify EGFR-downstream signaling alterations upon loss of Mig6 expression. We also treated these mice with erlotinib to examine regression of tumors. There was delay in regression of lung tumors upon erlotinib treatment in Mig6 knockout background. We are further validating this finding now and also conducting in vitro experiments in lung adenocarcinoma cell lines to demonstrate how Mig6 expression modulates TKI sensitivity in mutant EGFR-expressing lung adenocarcinoma cells.