EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation

Abstract

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.

Keywords: EGFR targeted therapy; NSCLC; TKIs; advanced; mutation; resistance..

Figure 1

Ways to leave your EGFR inhibitor: Biochemical pathways leading to resistance to small molecule EGFR drugs such as gefitinib and erlotinib. (A) Structures of two approved EGFR TKIs, gefitinib and erlotinib, used in the treatment of NSCLC. (B) Ribbon diagram of wild-type human EGFR (PDB code 2ITY), illustrating binding of gefitinib to the active site of the kinase. The magenta ball-stick (located just above the gefitinib molecule in the active site) indicates the gatekeeper residue (threonine790) that is commonly mutated to methionine (T790M), resulting in reduced inhibitor binding and drug resistance. (C) Simplified pathway diagram of EGFR signaling through RAS/MEK/ERK and PI3K/PDK1/AKT indicating the points of mutation/amplification in EGFR TKI resistance as reported by Sequist and colleagues. The resistance mechanisms include the EGFR T790M gatekeeper mutation, amplification of EGFR T790M, MET amplification, and PI3KCA mutation (note that additional epithelial to mesenchymal transition changes and transformation from the NSCLC to the SCLC phenotype also lead to resistance but are not covered by this illustration). The illustration also shows the FAS/NF-kB signaling arm downstream of the FAS death receptor that was shown to be important in TKI resistance by Bivona and colleagues. Reprinted from Cancer Cell, 19, Paul Workman and Paul A. Clarke, “Resisting Targeted Therapy: Fifty Ways to Leave Your EGFR”, 437-440, 2011, with permission from Elsevier.