This will undoubtedly accelerate progress in understanding the key determinants of treatment response in patients and enable the rational design of more effective therapeutic strategies to enhance clinical responses. such that the cells die without it (and treatment resistance. This challenge provides strong motivation to discover the molecular mechanisms that tumors use to evade driver oncogene inhibition. The identification of these molecular events pinpoints potential biomarkers of response to oncogene inhibitor treatment and rational therapeutic targets to prevent or overcome resistance to oncogene inhibition in patients. Lung cancers with activating mutations in the kinase domain name of EGFR serve as a paradigm for the field of targeted therapeutics and precision cancer medicine. Tumors from patients with advanced non-small cell lung cancer (NSCLC) are routinely screened for the presence of these mutations in EGFR, which most commonly occur in exon 19 or exon 21 in the form of an in-frame deletion or a point mutation (L858R), respectively. These somatic mutations in EGFR occur in approximately 10C30 percent of NSCLC patients (Physique 1A)(1). In EGFR mutant lung cancer patients with advanced disease, treatment with an EGFR kinase inhibitor (erlotinib or gefitinib) is usually superior to standard cytotoxic chemotherapy and has therefore become first-line therapy (2). While the vast majority of patients initially respond to EGFR TKI treatment, acquired resistance to therapy inevitably develops in patients. Prior work by several groups has uncovered the cause of acquired resistance in many cases. In approximately 50C60 percent of cases, the mechanism of acquired resistance to EGFR TKI therapy is the acquisition of a 1-Azakenpaullone second site T790M gate keeper mutation in the kinase domain name of EGFR, in addition to the primary activating kinase domain name mutation (3, 4). The second site T790M mutation in 1-Azakenpaullone EGFR alters the binding of erlotinib and gefitinib to the ATP-binding pocket and therefore these inhibitors are unable to block EGFR signaling. Other mechanisms of acquired resistance to erlotinib and gefitinib include: 1) upregulation of the AXL kinase in approximately 20C25 percent of cases (5), 2) amplification of the MET kinase in approximately 5 percent of cases (3, 4), 3) activating mutations in the PIK3CA gene in approximately 5% of cases(6), and 4) histologic and phenotypic transformation to small cell lung cancer in approximately 5 percent of cases (6). The mechanisms of acquired resistance to first line EGFR TKI treatment are unclear in the remaining 15C20 percent of cases. Moreover, the potential ways in which EGFR mutant lung cancers may evade treatment with next generation EGFR kinase inhibitors developed to overcome EGFR T790M driven resistance and that 1-Azakenpaullone are entering into the clinic are unknown. Two elegant studies by Ercan and colleagues (7) and by Takezawa and colleagues (8) in the current issue of shed new light around the mechanisms of acquired resistance to EGFR kinase inhibitors. Open in a separate window Open in a separate window Physique 1 Mechanisms of acquired resistance to EGFR inhibitors and emerging pharmacologic approaches to overcome resistance(A) The relative frequency of specific oncogenic driver mutations in lung adenocarcinomas. Red wedge indicates the frequency of somatic activating mutations in EGFR (L858R or in frame exon 19 deletion). (B) The spectrum and frequency of known drivers of acquired resistance to EGFR inhibitor therapy in lung cancer. Two new drivers 1-Azakenpaullone of acquired resistance are described in 1-Azakenpaullone this issue of amplification was seen in ~ 5% of patients (Ercan et al.) and amplification in ~ 12% of patients (Takezawa et al). Transformation to small cell lung cancer and epithelial to mesenchymal transition (EMT) have also been described as resistance mechanisms, however the frequency and degree to which these events drive EGFR TKI acquired resistance and the molecular pathways underlying these events have not been fully defined. (C) Schematic of pathways to EGFR inhibitor acquired resistance and pharmacologic approaches in development to overcome them. EGFR T790M mutation is the dominant driver of EGFR inhibitor resistance (50C60%). Second generation EGFR TKI inhibitors BIBW2992 (afatinib), PF299804 (dacomitinib), and WZ4002 covalently bind to EGFR and have shown promise as EGFRT790M inhibitors in preclinical studies. HER2 amplification may promote acquired resistance through heterodimerization with EGFR and activation of downstream signaling events (i.e. ERK and AKT). The combination of BIBW2992 together with the EGFR monoclonal antibody cetuximab or panitumumab can inhibit both EGFR and HER2 activity in cellular and murine models of EGFR-mutant driven lung cancer. amplification leads to increased ERK expression and elevated phospho-ERK levels. This may promote acquired resistance by promoting EGFR internalization. Inhibition of MEK activity by GSK-1120212 decreases ERK phosphorylation and overcomes acquired resistance driven by ERK overexpression in cellular and murine models. Upregulation AXL kinase activity occurs in Neurod1 20C25% of patients with acquired resistance to EGFR inhibitors and.