ReviewImpact of EGFR mutation analysis in non-small cell lung cancer
Introduction
Lung cancer is the leading cause of cancer-related death in many countries around the world including Japan [1], [2]. Non-small cell lung cancers (NSCLCs) account for approximately 80% of lung cancers and the most effective treatment for them is surgery when the tumor is confined to primary site with minimal regional lymph node involvement. However, only small portion of total NSCLC cases are operable and even patients with early stage of lung cancer who undergo curative surgery develop recurrence. Platinum-based chemotherapy is the standard therapy for advanced or recurrent NSCLCs, but the results of the treatment are still unsatisfactory [3]. Therefore, more effective treatments are urgently needed for advanced or recurrent NSCLCs.
As one of the new therapeutic strategies to improve the outcome of treatment for NSCLCs, targeting epidermal growth factor receptor (EGFR) was considered because EGFR is frequently overexpressed and aberrantly activated in NSCLCs [4]. The presence of activating mutations in EGFR was initially reported in 2004 [5], [6], [7]. Following these reports, various groups confirmed and extended these findings [8], [9], [10], [11], [12], [13], [14], [15]. The finding of these mutations within kinase domain of EGFR gene in lung adenocarcinomas is of great clinical interest, because many of these tumors are highly sensitive to EGFR-tyrosine kinase inhibitors (TKIs) [5], [6], [7]. While most of these tumors initially respond to EGFR-TKIs, vast majority of them finally become resistant to drug treatment. Second-site point mutation in EGFR (T790M) was reported to lead the resistance to TKIs in EGFR-mutant NSCLCs [16], [17]. More recently, the amplification of MET proto-oncogene was also reported to contribute to the acquired resistance [18], [19] and MET amplification was shown to occur independently of EGFR T790M mutations [18], [19]. MET is a heterodimeric transmembrane receptor tyrosine kinase (RTK) for the hepatocyte growth factor [20], [21]. Recently Guo et al. [22] reported that multiple RTKs are activated in lung cancer cell lines with EGFR mutation or MET amplification.
From the point of view of the molecular pathogenesis, it is also important to elucidate the relationship between EGFR mutations and other molecular alterations such as other EGFR-related gene mutations or aberrant methylation in tumor suppressor genes (TSGs), because a specific interaction of genetic and epigenetic alterations has been reported in colorectal cancers, suggesting the specific interaction between mutations and aberrant methylation [23].
In this review, we discuss the significance of EGFR mutation analysis in NSCLCs, focusing on the relationship among EGFR mutations, response to TKIs, the activation of multiple RTKs, other molecular alterations such as methylation and acquired resistance including EGFR T790M mutation and MET amplification.
Section snippets
EGFR mutational subtypes
EGFR mutations mainly exist in exons 18–21, the first four exons encoding tyrosine kinase domain (Fig. 1A). The majority of EGFR mutations consist of deletions in exon 19 and point mutation (L858R) in exon 21 [24]. In exon 19, there are over 20 variant types of deletion. As minor EGFR mutations, we also see the mutation at codon 719 (exon 18) and in-frame insertion mutations in exon 20. According to the data of compiled publications, 569 mutations were found in 2880 lung cancer patients and
Biological significance of EGFR mutations and the activation of multiple RTKs
Mutations in exons 19 and 21 lead to the constitutive autophosphorylation, thus activation of EGFR [26], [27]. Mutant EGFR is reported to selectively activate Akt and signal transducer and activator of transcription protein (STAT) signaling pathways that promote cell survival but less effect on the mitogen-activated protein kinase (MAPK) pathway that induces proliferation [28]. Distinct mutational patterns result in different tumorigenicity and response to TKI according to in vitro analysis [26]
EGFR mutations and sensitivity to EGFR-TKIs
The reason why the finding of EGFR mutations conferred a great impact on the clinicians and researchers is that lung cancers harboring this feature showed a dramatic response to EGFR-TKIs [5], [6], [7]. High response rates (around 70%) in patients with EGFR mutations to gefitinib were confirmed in the recently published prospective phase II studies ([33], [34], [35], [36] and Fig. 2). Besides, several reports indicate that patients with EGFR mutations have a significantly longer survival than
Increased EGFR gene copy number
In addition to mutations, increased gene copy number is another mechanism of oncogene activation. Cappuzzo et al. [51] first reported that an increase in the EGFR gene copy number, as measured by fluorescence in situ hybridization (FISH), is more predictive of patient survival after gefitinib treatment than EGFR mutations. However, this report does not necessarily refute the role of EGFR mutations as predictive factors, because EGFR mutations failed only to significantly affect overall survival
Relationship between EGFR mutations and alterations of other related genes
In addition to EGFR, other related gene alterations are important issues regarding tumorigenesis of lung. Mutations of EGFR and KRAS are reported to be mutually exclusive [8], [10]. Besides, there are a few reports that any of EGFR, HER2, KRAS or BRAF mutations occur simultaneously in individual patients, indicating that at least one activating mutation in the EGFR–RAS–RAF signaling pathway may be sufficient for the pathogenesis of many lung cancers. By contrast, PIK3CA mutations, which are
EGFR mutations and other molecular alterations
Epigenetic alteration of TSGs including aberrant methylation is an important mechanism in human carcinogenesis [61]. We previously reported that methylation of p16 and CDH13 genes is less methylated in EGFR-mutant adenocarcinomas than in EGFR-wild-type adenocarcinomas. In addition, the degree of methylation represented with methylation index is lower in EGFR-mutant tumors than in EGFR-wild-type tumors. As for prognosis, Brock et al. [62] recently reported that the methylation of p16 and CDH13
Acquired resistance to TKIs and MET amplification
Even the patients with EGFR-activating mutations initially respond to TKIs dramatically, the vast majority of them develop the acquired resistance to TKIs. In approximately half of these cases, the acquired resistance to TKIs is due to the second-site point mutation of the EGFR gene at codon 790 in exon 20 (T790M) [16], [17], [65], [66]. We reported that T790M is present in a very small fraction (0.5%) of patients without history of gefitinib treatment [67]. We developed an assay for the
Conclusions
The development of drug therapies that inhibit receptor tyrosine kinases, especially EGFR-TK, and the discovery of EGFR gene mutations have provided a great opportunity to develop individualized therapies for NSCLCs. Understanding the molecular backgrounds of EGFR and other targeted genes that determine sensitivity and resistance to a certain drug will develop the strategies for the treatment of lung cancer. Further understanding of EGFR and its related genes will be essential so as to decrease
Conflict of interest
TM received honoraria of less than $10,000 per year from AstraZeneca, Chugai Pharmaceuticals, Bristol-Meyers Squibb, Sanofi-Aventis, Taiho Pharmaceuticals, Kyowa Hakko.
Acknowledgment
This work was supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan 18390386 (to TM) and 18790993 (to ST).
References (72)
100 years of lung cancer
Respir Med
(2006)- et al.
The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies
Cancer Cell
(2006) - et al.
Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer
J Thorac Oncol
(2007) - et al.
A rapid, sensitive assay to detect EGFR mutation in small biopsy specimens from lung cancer
J Mol Diagn
(2006) - et al.
Detection of EGFR gene mutations using the wash fluid of CT-guided biopsy needle in NSCLC patients
J Thorac Oncol
(2008) - et al.
PTEN and PIK3CA expression is associated with prolonged survival after gefitinib treatment in EGFR-mutated lung cancer patients
J Thorac Oncol
(2006) - et al.
Mutations and addiction to EGFR: the Achilles ‘heal’ of lung cancers?
Trends Mol Med
(2004) - et al.
Cancer statistics 2008
CA Cancer J Clin
(2008) - et al.
Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer
N Engl J Med
(2002) - et al.
A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor
Clin Cancer Res
(2001)
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
N Engl J Med
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy
Science
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
Proc Natl Acad Sci USA
Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications
Cancer Res
EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment
J Clin Oncol
Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers
J Natl Cancer Inst
Activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor are associated with improved survival in gefitinib-treated chemorefractory lung adenocarcinomas
Clin Cancer Res
High frequency of epidermal growth factor receptor mutations with complex patterns in non-small cell lung cancers related to gefitinib responsiveness in Taiwan
Clin Cancer Res
The relationship between epidermal growth factor receptor mutations and clinicopathologic features in non-small cell lung cancers
Clin Cancer Res
Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer
Clin Cancer Res
Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma
Br J Cancer
EGFR mutation and resistance of non-small-cell lung cancer to gefitinib
N Engl J Med
Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain
PLoS Med
MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling
Science
MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib
Proc Natl Acad Sci USA
Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors
Proc Natl Acad Sci USA
Targeting the c-Met signaling pathway in cancer
Clin Cancer Res
Signaling networks assembled by oncogenic EGFR and c-Met
Proc Natl Acad Sci USA
Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype
Proc Natl Acad Sci USA
Mutations of the epidermal growth factor receptor gene and related genes as determinants of epidermal growth factor receptor tyrosine kinase inhibitors sensitivity in lung cancer
Cancer Sci
The impact of sex and smoking status on the mutational spectrum of epidermal growth factor receptor gene in non small cell lung cancer
Clin Cancer Res
Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants
PLoS Med
Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification
Cancer Res
Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways
Science
Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib
Clin Cancer Res
Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence
J Clin Oncol
Cited by (104)
RadGenNets: Deep learning-based radiogenomics model for gene mutation prediction in lung cancer
2022, Informatics in Medicine UnlockedCitation Excerpt :In NSCLC, the patient’s gene structure tends to change this change is known as “mutation”. The three major types of genes mutation are epidermal growth factor receptor (EGFR) [20], Kirsten rat sarcoma virus (KRAS [21], and Anaplastic lymphoma kinase (ALK) [22]. EGFR mutation refers to a chemical that inhibits the action of the epidermal growth factor receptor, a protein that aids in cell growth and division [23].
Overexpression of YAP1 in EGFR mutant lung adenocarcinoma prior to tyrosine kinase inhibitor therapy is associated with poor survival
2018, Pathology Research and PracticeCitation Excerpt :Epidermal growth factor receptor (EGFR) gene is one of the driver oncogenes for lung adenocarcinoma (LADC). The rate of EGFR mutation in non-small cell lung cancer (NSCLC) has been documented as 30–40% for Asian and 2–8% for Western countries [1,2]. EGFR mutant NSCLC is characteristically associated with females, younger ages, non-smokers, adenocarcinoma histology, and East Asian races [3].
TGF-β/SMAD3 pathway stimulates sphingosine-1 phosphate receptor 3 expression: Implication of sphingosine-1 phosphate receptor 3 in lung adenocarcinoma progression
2016, Journal of Biological ChemistryCitation Excerpt :NOD-Scid mice (8 weeks old, female, Taconic) were used for H1793, athymic nude mice (8 weeks old, female, Harlan) were used for H1299 cells, and C57BL/6 mice (8 weeks old, female, The Jackson Laboratory) were used for Lewis lung carcinoma cells. Tumor volume was measured in two dimensions using calipers, and volume was determined using the formula width2 × length × 0.52 (49). For VPC23019 treatment, mice were randomized into two groups (six animals per group) 1 week after inoculation of tumor cells.
Detection EGFR exon 19 status of lung cancer patients by DNA electrochemical biosensor
2016, Biosensors and BioelectronicsFirst-, Second-, and Third-Generation Radiolabeled Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Positron Emission Tomography: State of the Art, a Systematic Review
2023, Cancer Biotherapy and Radiopharmaceuticals