Targeting EGFR in lung cancer: Lessons learned and future perspectives

Abstract

The development of individualized therapies has become the focus of current oncology research. Precision medicine has demonstrated great potential for bringing safe and effective drugs to those patients stricken with cancer, and is becoming a reality as more oncogenic drivers of malignancy are discovered. The discovery of Epidermal Growth Factor Receptor (EGFR) mutations as a driving mutation in non-small cell lung cancer (NSCLC) and the subsequent success of the tyrosine kinase inhibitors (TKI) have led the way for NSCLC to be at the forefront of biomarker-based drug development. However, this direction was not always so clear, and this article describes the lessons learned in targeted therapy development from EGFR in NSCLC.

DUOX1 mediates persistent epithelial EGFR activation, mucous cell metaplasia, and airway remodeling during allergic asthma

“…38, 39), the contribution of DUOX1 to allergic inflammation was found to be closely related to its role in persistent oxidant-dependent epithelial activation of EGFR and consequent production of neutrophil chemokines and type 2 cytokines such as IL-13, which results in promotion of neutrophilic inflammation, mucous metaplasia, subepithelial fibrotic remodeling, and central airway resistance. The importance of airway EGFR activation to these various features of allergic asthma is well recognized (11,15,17), but existing EGFR tyrosine kinase inhibitors have not been evaluated for clinical application in chronic lung diseases such as asthma, because of the broad role of EGFR in various organ systems and reported adverse effects that are tolerable in severe or fatal lung diseases, such as lung cancer, but not in lung diseases that are not immediately life-threatening (12,(18)(19)(20). The fact that DUOX1 expression is largely restricted to epithelial lineages (39), including the lung, renders it a more appealing therapeutic target, with the potential of avoiding unwanted side effects associated with EGFR inhibitors administered systemically.…”

“…However, these findings have not been translated into clinical use of available selective EGFR tyrosine kinase inhibitors in treatment of asthma, as EGFR tyrosine kinase inhibitors are associated with adverse effects, such as enhanced skin rash and inflammation (18). In addition, while EGFR tyrosine kinase inhibitors are used successfully in the treatment of lung cancers, they commonly induce acquired resistance due to the promotion of secondary EGFR mutations (19), thus significantly limiting their use in less life-threatening chronic diseases. A recent clinical trial using the EGFR inhibitor BIBW 2948 in patients with COPD indicated efficacy with respect to inhibiting EGFR activation and a tendency toward reducing mucous metaplasia but was terminated due to adverse effects such as reversible liver enzyme elevation and decreased forced expiratory volume in 1 second (FEV1) in some patients (20).…”

Antitumor activity of high-dose pulsatile gefitinib in non-small-cell lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors

“…Cells were seeded at a density of 1.0x10 6 cells/well into 6-well plates for 24 h. The experiment group was divided into control (0 nM), 30, 60 and 120 nM in PC9; control, 20, 40 and 80 µM in H1975; and control, 25, 50 and 100 µM in H1650. Following incubation with or without gefitinib for 48 h at 37˚C, cells were harvested and lysed in ice-cold lysis buffer.…”

“…Inhibition of mutated epidermal growth factor receptor (EGFR) is considered to be key in the treatment of NSCLC (6). It has been established that EGFR-tyrosine kinase inhibitors (TKI) are superior to standard chemotherapy as a first-line treatment for patients with an EGFR mutation (7,8).…”

Early Diagnosis with 11-Gene Panel Screening for Non Small Cell Lung Cancer

“…And the test of gene expression in precision medicine worked as guidelines of targeted therapy. Therapeutic options for patients diagnosed with lung cancer have significant growed due in major part to improved technological ability of diagnosis [6,7]. Early stage diagnosis and surgery of NSCLC patients could result in a 5-year survival rate of up to 55-80% [8].…”