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

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.

Potential mechanism of primary resistance to icotinib in patients with advanced non–small cell lung cancer harboring uncommon mutant epidermal growth factor receptor: A multi‐center study

“…Circulating tumor DNA (ctDNA) in peripheral blood is becoming increasingly popular in comparison with tumor biopsy. There are several reasons why ctDNA is superior to tumor tissue biopsy: it is relatively non–invasive, efficient and economical, and a promising tool to monitor dynamically and could possibly replace tissue biopsy in future . Other specimens including tumor cells in malignant pleural effusion could also be used to analyze genetic profiling if ctDNA is unavailable.…”

The Co-Expression of Programmed Death-Ligand 1 (PD-L1) in Untreated EGFR-Mutated Metastatic Lung Adenocarcinoma

“…According to the classification of histopathology, non-small-cell lung cancer (NSCLC) accounts for 85% of cases, and adenocarcinoma is the most common histological type of NSCLC (~50%) [2,3]. Active mutation in the epidermal growth factor receptor (EGFR) kinase domain has been well studied and is known to be the main oncogenic-driven mutation in lung adenocarcinoma [4,5]. The frequency of EGFR-driven mutations in lung adenocarcinoma rates ranges from 40% to 55% in East Asians [5,6].…”

“…Active mutation in the epidermal growth factor receptor (EGFR) kinase domain has been well studied and is known to be the main oncogenic-driven mutation in lung adenocarcinoma [4,5]. The frequency of EGFR-driven mutations in lung adenocarcinoma rates ranges from 40% to 55% in East Asians [5,6]. L858R and exon 19 deletion are the two types of the most frequent EGFR mutations and account for 90% of all EGFR mutations [5][6][7].…”

Cucurbitacin E inhibits the Yes‑associated protein signaling pathway and suppresses brain metastasis of human non‑small cell lung cancer in a murine model

“…Treatment options for those patients whose tumors lack targetable mutations remain quite limited. For example, erlotinib, an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is an effective target therapy for brain metastatic lung adenocarcinoma harboring EGFR exon 19 deletion or exon 21 L858R mutations (5)(6)(7)(8). Anaplastic lymphoma kinase (ALK) inhibitors including ceritinib and alectinib have better response rates than conventional chemotherapy for brain metastatic NSCLC patients with ALK-rearrangement mutation (9,10).…”