Mutations of the epidermal growth factor receptor tyrosine kinase domain and associations with clinicopathological features in non-small cell lung cancer patients

Somatic tyrosine kinase (TK) domain mutations of the epidermal growth factor receptor (EGFR) gene are associated with sensitivity of non-small cell lung cancer (NSCLC) to tyrosine kinase inhibitors (TKI's), however their incidence in distinct populations is not clarified. We sequenced exons 18-21 of the EGFR TK domain from 60 Greek and Czech patients, enrolled in an adjuvant chemotherapy trial following total resection for stages I-IIIa disease. Somatic mutations were found in 9/60 patients (15.0%), several being novel. EGFR mutations were more common in Stage I tumors (p = 0.023), they were also more common in women and never smokers; however, no other significant association of clinicopathological features with mutations was found. Median TTP and OS of patients with and without mutations were 13.2 and 40 months compared to 22.9 and 43.2 months, respectively. These differences were not statistically significant. K-ras (5/60, 8%) and EGFR mutations were found to be mutually exclusive. We identified a wide spectrum of somatic EGFR TK mutations reporting a relatively high incidence (15%) in NSCLC patients of Greek and Czech origin. As ethnicity seems to be a factor for the origin of these mutations, further studies in distinct populations are warranted.     

Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting epidermal growth factor receptor (EGFR) signaling has proven to be an effective strategy for treating non-small cell lung cancer (NSCLC) patients and the first generation of agents developed for this purpose, gefitinib and erlotinib, stimulated a unique escalation in both biologic and clinical research within the field. Second-generation EGFR-targeted agents that aim to further improve patient outcomes are now in preclinical and clinical trials. This review discusses four promising agents that are currently being studied in NSCLC: EKB-569, HKI-272, CI-1033, and ZD6474.     

Gefitinib-sensitive mutations of the epidermal growth factor receptor tyrosine kinase domain in chinese patients with non-small cell lung cancer.

PURPOSE: Studies have shown that mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain are associated with response of lung cancer to gefitinib (Iressa, AstraZeneca Corp., Shanghai, China). A higher incidence of EGFR mutation was observed in non-small cell lung cancer (NSCLC) patients of Japanese origin compared with those of American origin. However, no data about such mutations in Chinese patients with NSCLC could be obtained. METHODS: Primary NSCLC tissues were obtained for analysis of mutations in exons 18 to 21 of EGFR from a total of 76 patients, of whom 54 did not receive gefitinib therapy and 22 did. PCR products were sequenced directly and mutations were confirmed by an independent PCR and sequence analysis. All types of mutation were cloned and sequenced. RESULTS: A total of 10 types of mutation were found in the series of patients, including two different silent mutations in exon 20 from 11 patients. More than half of the silent mutations (6 of 11) in exon 20 coexisted with other mutations. Mutations were more frequent in adenocarcinoma (17 of 35; 48.6%) compared with squamous carcinoma (1 of 19; 5.3%) among untreated patients. Similar mutations were observed in all seven gefitinib-treated patients with partial response, and no mutations were detected in all eight patients with progressive disease (P < 0.001), except two silent mutations. Three mutations were observed in seven patients with stable disease. CONCLUSIONS: Mutations in the epidermal growth factor receptor tyrosine kinase domain in lung adenocarcinomas from Chinese patients were more frequent than reported previously in lung adenocarcinomas from American patients. Such mutations were well correlated with tumor response to gefitinib.     

Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective therapies for non-small cell lung cancer patients whose tumors harbor somatic mutations in EGFR. All patients, however, ultimately develop resistance to these agents. Thus, there is a great need to understand how patients become resistant to develop effective therapies for these cancers. Studies over the last few years have identified two different EGFR tyrosine kinase inhibitor resistance mechanisms, a secondary mutation in EGFR, EGFR 790M, and amplification of the MET oncogene. These findings have led to clinical trials using newly designed targeted therapies that can overcome these resistance mechanisms and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for non-small cell lung cancer patients.     

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

非小细胞肺癌获得性表皮生长因子受体酪氨酸激酶抑制剂耐药治疗疗效观察

目的探讨非小细胞肺癌(NSCLC)患者获得性表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药后后续化疗联合沙利度胺和化疗序贯EGFR-TKIs治疗的疗效。方法选取2016年1月至2017年2月间安徽省芜湖市第二人民医院收治的经EGFR-TKIs治疗起效并出现获得性耐药的41例NSCLC患者,采用随机数字生成法分为A组和B组。A组21例患者采用多西他赛、培美曲赛和顺铂化疗,联合沙利度胺口服治疗; B组20例患者采用多西他赛、培美曲赛和顺铂化疗,序贯EGFR-TKIs治疗。比较两组患者的近期疗效、中位无进展生存时间(PFS)及不良反应。结果两组患者近期疗效比较,差异无统计学意义(P> 0. 05)。两组患者中位PFS比较,差异无统计学意义(P> 0. 05)。A组患者便秘发生率高于B组,恶心、呕吐发生率低于B组,组间差异均有统计学意义(均P <0. 05)。结论常规化疗联合沙利度胺和常规化疗序贯EGFR-TKIs治疗均可作为获得性EGFR-TKIs耐药NSCLC晚期患者的后续治疗方案,临床可根据实际情况选用。     

Mutations of the epidermal growth factor receptor in non-small cell lung cancer -- search and destroy

The targeting of the ATP binding pocket of the epidermal growth factor receptor (EGFR) tyrosine kinase, by the small molecule drugs gefitinib and erlotinib, represents a promising new therapeutic strategy in non-small cell lung cancer. However, it is now apparent that only a subset of patients responds to such treatment. Two publications in early 2004 reported the presence of activating mutations in the EGFR tyrosine kinase gene conferring exquisite sensitivity to these drugs. Several publications have since reported prospective data consistent with this finding. This brief review summarises the mutation data from 15 such studies in terms of mutation frequency by clinicopathological features and correlation with response to tyrosine kinase inhibition. A new paradigm for the routine detection of such mutations is needed to facilitate patient selection for treatment and further studies.     

Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer metastatic to the brain

Brain metastases are a common and devastating consequence of disease progression in patients with non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib have shown efficacy in patients with NSCLC and brain metastases. The cerebrospinal fluid (CSF) exposure to these drugs is a small fraction of the plasma levels achieved with standard doses, but disruption of the blood-brain barrier in the presence of central nervous system metastases is likely to lead to locally increased drug concentration, and dose escalation to boost CSF exposure has documented clinical efficacy. The use of gefitinib and erlotinib in this setting is reviewed here, including evidence from case reports, case series, and single-arm phase II trials. High response rates in the brain are seen in patients with EGFR mutation, or in populations in which this genotype is expected. By contrast, activity in the context of documented wild-type EGFR in disease metastatic to the brain is not common. These drugs may potentiate the effectiveness of radiotherapy to the brain, and their use may also delay development of disease within the brain.     

Targeting the epidermal growth factor receptor in non-small cell lung cancer

The epidermal growth factor receptor (EGFR) has been implicated in a multiplicity of cancer-related signal transduction pathways like cellular proliferation, adhesion, migration, neoangiogenesis and apoptosis inhibition, all of them important features of cancerogenesis and tumour progression. The inhibition of this receptor has been discovered as a suitable pharmaceutical intervention aimed at interrupting tumour activity. In cancer, both monoclonal antibodies and small molecules with anti-tyrosine kinase activity have been assessed in several trials with significant efficacy in clinical applications. The current review focuses in particular on the clinical data of EGFR inhibition in non-small cell lung cancer with emphasis on tyrosine kinase inhibition.     

表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌的耐药机制

表皮生长因子受体酪氨酸激酶抑制剂（ EGFR-TKI）在非小细胞肺癌的治疗中具有重要地位,但有研究发现患者会对EGFR-TKI产生原发性耐药或获得性耐药。目前发现获得性耐药的多种机制最终都导致表皮生长因子受体的下游信号通路被重新激活。肝X受体激动剂对表皮生长因子受体最重要的下游通路PI3K-Akt-NF-κB的多个主要环节均有不同程度的抑制作用,有望逆转EGFR-TKI的继发耐药。     

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

Recent discovery of mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma greatly stimulated biomarker research on predictive factors for EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Although patients with activating mutations of the EGFR generally respond to EGFR TKIs very well, it is natural to assume that there is no sole determinant, considering great complexity and redundancy of the EGFR pathway. Subsequently, roles of different types of EGFR mutations or mutations of genes that are members of the EGFR pathway such as KRAS and HER2 have been evaluated. In this review, we summarize the recent findings about how mutations of the EGFR and related genes affect sensitivity to EFGR-TKIs. We also discuss molecular mechanisms of acquired resistance to EGFR-TKIs that is almost inevitable in EGFR-TKI therapy. The door for genotype-based treatment of lung cancer is beginning to open, and through these efforts, it will be possible to slow the progression of lung cancer and eventually, to decrease mortality from lung cancer. ( Cancer Sci 2007; 98: 1817–1824)     

Mutation in the tyrosine kinase domain of epidermal growth factor receptor is a predictive and prognostic factor for gefitinib treatment in patients with non-small cell lung cancer.

PURPOSE: Mutations in epidermal growth factor receptor (EGFR) can be used to predict the tumor response of patients receiving gefitinib for non-small cell lung cancer (NSCLC). We investigated the association between mutations in EGFR tyrosine kinase domain and tumor response and survival in gefitinib-treated NSCLC patients. EXPERIMENTAL DESIGN: EGFR mutations in exons 18 to 21 were analyzed by DNA sequencing of paraffin-embedded tumor tissues from gefitinib-treated NSCLC patients. The results were correlated with clinical variables. RESULTS: EGFR mutations were found in 61.1% (33 of 54) of cases; response rate and disease control rate were 56.8% and 68.5%, respectively. There was no significant difference in mutation rates between adenocarcinoma (29 of 43) and nonadenocarcinoma (4 of 11; P = 0.085). However, all four nonadenocarcinomas with EGFR mutations had no response to gefitinib. Presence of EGFR mutations was the only independent predictor for disease control (P = 0.003) and tumor response (P = 0.017) in multivariate analysis; positive predictive values were 87.9% and 70.8% and negative predictive values were 61.9% and 69.2%, respectively. In comparison with patients whose tumor was negative for EGFR mutations, patients with EGFR mutations had better progression-free survival (median, 7.6 versus 1.7 months; P = 0.011) and overall survival (median, 14.7 versus 4.7 months; P = 0.046). CONCLUSIONS: Mutations in EGFR tyrosine kinase correlate with treatment response and survival in gefitinib-treated NSCLC patients and can be used as a predictive and prognostic factor. Thus, analysis of EGFR tyrosine kinase mutations in lung adenocarcinoma is of clinical significance, as it can permit the customization of treatment with EGFR tyrosine kinase inhibitors.     

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) mutations are well-described drivers of non-small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have become key components of the NSCLC front-line treatment landscape. Tumors inevitably develop resistance to these agents, and development efforts continue to focus on identifying mechanisms of resistance and drugs to target these mechanisms.

Areas covered: With several EGFR TKIs approved for use in the first-line or in later-line settings, an understanding of the efficacy and safety of these inhibitors in various populations is warranted. Furthermore, given the frequent emergence of drug resistance in NSCLC, examination of tumor tissue throughout the disease course provides the opportunity to select treatments based on the tumor’s mutation profile. Here, we discuss: key efficacy and safety findings for approved and investigational EGFR TKIs; known mechanisms of resistance, particularly the T790M acquired EGFR mutation; and recent advances in EGFR mutational testing that may facilitate less invasive tissue testing and guide treatment selection.

Expert commentary: The expanding armamentarium of EGFR TKIs, improvements in the understanding of resistance mechanisms and technological developments in the molecular analysis of tumors may help render EGFR mutation-positive NSCLC a chronic disease in many patients by facilitating optimal sequential therapy.     

Effects of icotinib, a novel epidermal growth factor receptor tyrosine kinase inhibitor, in EGFR-mutated non-small cell lung cancer

Epidermal growth factor receptor (EGFR) is one of the most promising targets for non-small cell lung cancer (NSCLC). Our study demonstrated the antitumor effects of icotinib hydrochloride, a highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), in two EGFR-mutated lung cancer cell lines compared to A549, a cell line without EGFR mutations. We incubated PC-9 and HCC827 human lung cancer cell lines both with (E746-A750) mutations with various concentrations of icotinib and gefitinib for 48 h. Cell proliferation and migration were determined using a real-time cell invasion and migration assay and cytotoxicity assay. Apoptosis was assessed by measuring Annexin V staining using flow cytometry. The antitumor effects of icotinib compared to gefitinib were similar and were most effective in reducing the proliferation of EGFR-mutated cells compared to non-mutated controls. Our results suggest the possibility of icotinib as a new therapeutic agent of EGFR-mutated cancer cells, which has the potential to be used in the first-line treatment of EGFR-mutated NSCLC.     

Primary and acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer: an update

Epidermal growth factor receptor (EGFR) is a critical target in the treatment of nonsmall cell lung cancer (NSCLC). The mutations involving EGFR are more prevalent in patients of Asian ancestry, women, never smokers, and those with adenocarcinoma histology. Primary mechanism of resistance to EGFR-TKIs includes in frame insertion mutation in exon 20, de novo T790M mutation also on exon 20, activating mutations in KRAS, loss of PTEN, and amplification of c-MET whereas acquired resistance results from development of secondary alteration in ATP domain of T790M. There are many novel targeting agents in development to overcome resistance to EGFR TKIs.     

Update on epidermal growth factor receptor mutations in non-small cell lung cancer.

In 2004, several investigators reported that somatic mutations in the epidermal growth factor receptor gene were associated with clinical responses to erlotinib and gefitinib in patients with non-small cell lung cancer. Since then, multiple groups have examined the biological properties that such mutations confer as well as the clinical relevance of these mutations in patients with non-small cell lung cancer. Although a tremendous amount of knowledge has been gained in the past 2 years, there remain a number of important epidemiologic, biological, and clinical questions.     

A willingness-to-pay study of oral epidermal growth factor tyrosine kinase inhibitors in advanced non-small cell lung cancer

PURPOSE: Oral epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are new agents in the treatment of advanced non-small cell lung cancer (NSCLC). Phase II studies demonstrate objective tumor responses and symptom improvement, combined with minimal toxicity and the convenience of an oral agent. We evaluated patient utility through willingness-to-pay (WTP) for these agents in the treatment of advanced NSCLC in Canada. METHODS: Advanced NSCLC patients and healthy subjects participated in a structured interview and bidding exercise, reviewing current evidence supporting EGFR TKI therapy in advanced NSCLC and patient willingness-to-pay for treatment. RESULTS: Fifty-seven patients and 54 healthy subjects participated. The median amount both groups were willing to pay for a month of oral EGFR TKI therapy was $100 CAD (range $0-5000 per month). A minority of NSCLC patients received employment income, the majority relying on disability, pension income, and social assistance for financial support. Affordability of these agents was a key concern for both advanced NSCLC patients and healthy subjects. Univariate predictors of WTP included marital status, prior chemotherapy treatment, receiving pension income or financial social assistance. In multivariate analysis, only prior chemotherapy remained a significant predictor of WTP (p=0.049). CONCLUSION: Both advanced NSCLC patients and healthy subjects feel oral EGFR TKIs are worth paying for in the treatment of advanced NSCLC, but are willing to pay only a fraction of the market price. As many advanced NSCLC patients are financially disadvantaged, the potential for restricted access to newer therapies is of concern.     

Somatic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) abrogate EGFR-mediated radioprotection in non-small cell lung carcinoma

The epidermal growth factor receptor (EGFR) is an important determinant of radioresponse, whose elevated expression and activity frequently correlates with radioresistance in several cancers, including non-small cell lung carcinoma (NSCLC). We reported recently that NSCLC cell lines harboring somatic, activating mutations in the tyrosine kinase domain (TKD) of the EGFR exhibit significant delays in the repair of DNA double-strand breaks (DSB) and poor clonogenic survival in response to radiation. Here, we explore the mechanisms underlying mutant EGFR-associated radiosensitivity. In three representative NSCLC cell lines, we show that, unlike wild-type (WT) EGFR, receptors with common oncogenic TKD mutations, L858R or DeltaE746-E750, are defective in radiation-induced translocation to the nucleus and fail to bind the catalytic and regulatory subunits of the DNA-dependent protein kinase (DNA-PK), a key enzyme in the nonhomologous end-joining repair pathway. Moreover, despite the presence of WT EGFR, stable exogenous expression of either the L858R or the DeltaE746-E750 mutant forms of EGFR in human bronchial epithelial cells significantly delays repair of ionizing radiation (IR)-induced DSBs, blocks the resolution of frank or microhomologous DNA ends, and abrogates IR-induced nuclear EGFR translocation or binding to DNA-PK catalytic subunit. Our study has identified a subset of naturally occurring EGFR mutations that lack a critical radioprotective function of EGFR, providing valuable insights on how the EGFR mediates cell survival in response to radiation in NSCLC cell lines.