Abstract
Simple SummaryNon-small cell lung cancer (NSCLC) is the most common cancer in the world. For common EGFR mutations, treatment is based on different inhibitors. Despite the excellent disease control with inhibitors, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and some possible drug targets. Resistance mechanisms could be involved as gene mutations, amplifications or fusions, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of inhibitors and could be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.
Highlights
Lung cancer remains the most common cause of cancer deaths worldwide
As third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) osimertinib is currently used in first-line treatment for common EGFR-mutated Non-small cell lung cancer (NSCLC) patients, we focus on the mechanism of acquired resistance after such treatments [10]
It is becoming clear that sequencing a series of EGFR-TKIs is not an effective long-term strategy
Summary
Lung cancer remains the most common cause of cancer deaths worldwide. The molecular classification of non-small cell lung cancers (NSCLCs) leads to the discovery of oncogenic drivers, which could be targetable. Molecular Epidemiology of EGFR Mutations EGFR exons 18 to 24 encode the tyrosine kinase domain of EGFR, and EGFR activating mutations are located in four exons (18, 19, 20, 21) (Figure 1). These mutations are responsible for the constitutive activation of EGFR and the activation of several pathways, which lead to cell proliferation, among others. Their frequency is around 10 to 15% in Caucasian non-small cell lung cancers (NSCLC) and 30 to 50% in Asian NSCLC [1,2]. Three factors appear to complicate the estimation of the true frequencies of each EGFR mutation in clinics: molecular methods, the presence of complex mutations, and publications’ biases
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