Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

Abstract

Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

Figure 1. Pie chart of the frequency of driver oncogene mutations in lung adenocarcinomas from former/current smokers (left panel) and from never-smokers (right panel). Note the striking difference between the higher frequency of EGFR, ALK, ROS1, ERBB2, RET, BRAF (V600E), and NTRK1 mutations in never-smokers, and the higher frequency of KRAS mutations in smokers.

Figure 2. Epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC). A, Structure of the kinase domain of EGFR in complex with erlotinib (based on Protein Data Bank [PDB] accession code 1M17) and location of the most common EGFR mutations. B, Frequency, exon location, and sensitivity to EGFR inhibitors of the most common EGFR mutations. TKIs: tyrosine kinase inhibitors.

Figure 3. A, Mechanism of activation of the JAK/STAT, MAPK/ERK and PI3K/AKT pathways by epidermal growth factor receptor (EGFR) mutations and their inhibition by EGFR tyrosine kinase inhibitors (TKIs). B, Mechanisms of acquired resistance to EGFR TKIs in EGFR mutated non-small-cell lung cancer (NSCLC) with emphasis on the EGFR-T790M resistant mutation and oncogene bypass tracks that re-activate downstream signaling cascades.