Epidermal growth factor receptor mutation in combination with expression of MIG6 alters gefitinib sensitivity

We predicted and experimentally verified that Mig6, which is a known negative regulator of EGFR and specifically expressed in H1299L858R cells, synergized with gefitinib to suppress cellular growth. Computational analyses indicated that this inhibitory effect is amplified at the phosphorylation/dephosphorylation steps of MEK and ERK.Thus, we showed that L858R receptor mutation in combination with expression of its negative regulator, Mig6, alters signaling outcomes and results in variable drug sensitivity.The ErbB family receptors belong to the receptor tyrosine kinases (RTKs) and consist of four members; ErbB1 (also known as EGFR; epidermal growth factor receptor), ErbB2, ErbB3 and ErbB4 [1-4]. EGFR is distributed various tissues of the human body [5-7], and plays a critical role in the regulation of a variety of cellular responses ranging from cell differentiation, growth, proliferation, apoptosis, migration and adhesion [2,8].EGFR is frequently overexpressed in various human tumors including non-small-cell lung cancer (NSCLC) and is associated with poor outcome [9,10]. In many cases, enhanced EGFR signaling leads to abnormal cellular processes and often induces cancer [11,12]. Certain NSCLC patients have mutations at specific amino acid residues in the kinase domain of EGFR and show altered responsiveness to gefitinib (Iressa), an EGFR tyrosine kinase inhibitor. The L858R substitution (an arginine for leucine substitution at amino acid 858) is one of the most frequently reported mutations [13] and shows good responses to gefitinib [14-16]. It was reported that the L858R mutation enhances gefitinib sensitivity due to a structural change in the kinase domain resulting in an increased binding affinity of gefitinib for its ATP binding pocket in vitro [16]. On the other hand, a large scale binding assay using different types of kinases showed that the difference in binding affinity of the EGFR itself may not have a great effect on gefitinib sensitivity [17]. Based on