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.

Association between the histological subtype of lung adenocarcinoma, EGFR/KRAS mutation status and the ALK rearrangement according to the novel IASLC/ATS/ERS classification

“…With the increasing administration of targeted therapy, the driver genes harbored in LAC may receive increased consideration. Targeted therapy has been associated with great achievements towards improving the clinical outcomes of LAC patients (4). For example, targeted therapy has been shown to increase the median progression-free survival time of patients when compared with standard chemotherapy (5).…”

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

“…Certain other clinically-relevant kinase domain EGFR mutations, named by others as uncommon or atypical mutations, seem to be EGFR TKI sensitive in preclinical models (where they are transforming and activate the MAPK/PI3K signaling cascades) and in available published clinical reports (4,16,17). These mutations encompass EGFR-exon 18 indels/E709X (<0.5% of EGFR mutations), exon 18 G719X (~3% of EGFR mutations), exon 19 insertions (<0.5% of EGFR mutations), exon 20 A763_ Y764insFQEA (<0.5% of EGFR mutations), exon 20 S768I (<1.5% of EGFR mutations) and the exon 21 L861Q (~3% of EGFR mutations); either alone or compound with other EGFR mutations (19).…”

Small cell lung cancer transformation and the T790M mutation: A case report of two acquired mechanisms of TKI resistance detected in a tumor rebiopsy and plasma sample of EGFR-mutant lung adenocarcinoma

“…The use of mutant-selective inhibitors of EGFR, in addition to a combination of treatments and multi-targeting drugs, constitutes current clinical approaches for overcoming EGFR-TKI resistance in NSCLC (14,15). Therefore, the characterization of all the molecular resistant mechanisms occurring in the same patient is crucial to define a more effective therapeutic regimen.…”