Determining EGFR-TKI sensitivity of G719X and other uncommon EGFR mutations in non-small cell lung cancer: Perplexity and solution (Review)

Abstract

Mutations in epidermal growth factor receptor (EGFR) play critical roles in the pathogenesis of non-small cell lung cancer (NSCLC), and they are highly associated with sensitivity to tyrosine kinase inhibitors (TKIs). While the pathogenic and pharmacological characteristics of common mutations in EGFR have been thoroughly investigated, those of uncommon mutations remain to be elucidated. Traditional approaches to study common mutations by randomized controlled trials are not feasible for uncommon mutations owing to their rarity. Therefore, by systematically reviewing laboratory and clinical studies of the G719X mutation, one of the uncommon mutations, we concluded that the G719X mutation was intermediately sensitive to TKIs, with an average response rate of 35.1% (47/134). Moreover, accordingly, we proposed a comprehensive model to investigate uncommon mutations in EGFR. The model involves both basic and clinical components, composed of structural analyses, functional alterations, cell viabilities and animal models with various types of clinical studies. In this review, we systematically reviewed studies of the G719X mutation and put forward a research model that could be generalized to explore uncommon mutations in diseases associated with gene mutations.

Figure 1.

Mutation frequency and distribution in Asian and Caucasian populations. (A and B) Frequencies of various driver mutations in NSCLC patients of Asian and Caucasian populations; the data are referred from Kohno 2015 (14). (C and D) Distribution of different mutations among EGFR mutations in NSCLC patients of Asian and Caucasian populations; the data were generated by summarizing the results from previous studies (–22).

Figure 2.

The history of studies of G719X mutation in EGFR. 2G TKI, second generation of tyrosine kinase inhibitor; RR, response rate; wt, wild-type EGFR. Green, oncogenicity; red, TKI sensitive; orange, TKI intermediately sensitive; blue, TKI resistant.

Figure 3.

A comprehensive model to study uncommon mutations in EGFR. The system is comprised of both basic and clinical studies. Clinical studies include three parts: Case reports and series; Retrospective studies are reviews and meta-analyses to combine the data of RR and survival of patients with the G719X mutation; Prospective studies of observational ones or randomized controlled trials. There are two major issues in clinical studies: response to TKIs and survival data of patients. Laboratory studies are organized from mutant protein structures to functional changes, cell viability and animal models. Structural analyses by crystal diffraction or computational simulation determine the structures of mutant EGFR, EGFR-ATP complexes and EGFR-TKI complexes, to elucidate functional changes. Functional studies are categorized into four parts from the perspective of EGFR activation, including ligand biding, dimerization, kinase activity and downregulation, while the latter two are further subdivided as illustrated. For cell viability, the two aspects of proliferation and apoptosis are considered. Animal models involve GEMMs and tumor-cell inoculated xenografts including PDX models, which are discussed in terms of tumor sizes and animal survival. TKI treatment is introduced into all experiments on three levels. With basic and clinical studies integrated together, a complete evidence system is formed to draw conclusions regarding the pathogenic and pharmacological properties of uncommon mutations with high reliability. ∆EGFR, mutant EGFR.