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

2005 ◽  
Vol 23 (4) ◽  
pp. 857-865 ◽  
Author(s):  
Antonio Marchetti ◽  
Carla Martella ◽  
Lara Felicioni ◽  
Fabio Barassi ◽  
Simona Salvatore ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Direct Sequencing ◽  
Kinase Domain ◽  
Small Cell ◽  
Sscp Analysis ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Lung Carcinomas ◽  
Lung Adenocarcinomas

Purpose It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non–small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. Patients and Methods We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach—direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. Results There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. Conclusion Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.

scholarly journals Primary Erlotinib Resistance in a Patient with Non-Small Cell Lung Cancer Carrying Simultaneous Compound EGFR L718A, Q849H, and L858R Mutations

2021 ◽  
Vol 12 (1) ◽  
pp. 164-174
Author(s):  
Hanifeh Mirtavoos-mahyari ◽  
Elham Rismani ◽  
Alireza Sarkar Lotfabadi ◽  
Azizollah Abbasi Dezfouli ◽  
Kambiz Sheikhy ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Domain ◽  
Small Cell ◽  
Dynamics Simulation ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Tyrosine Kinase

Abstract Nowadays, mutations in the epidermal growth factor receptor (EGFR) kinase domain are studied in targeted therapy of non-small cell lung cancer (NSCLC) with EGFR tyrosine kinase inhibitors including gefitinib and erlotinib. The present study reports a rare case of a patient harboring three simultaneous EGFR mutations (L718A, Q849H, and L858R). The development of erlotinib resistance was detected in the subsequent treatment. Using a computational approach, the current study investigated the conformational changes of wild-type and mutant EGFR's kinase domains in the interaction with erlotinib. Their binding modes with erlotinib were elucidated during molecular dynamics simulation, where higher fluctuations were detected in the mutated forms of the EGFR tyrosine kinase domain. Prediction of stability and functional effect of mutations revealed that amino acidic substitutions have decreased the protein stability as well as the binding affinity to erlotinib. These results may be useful for a recommendation of EGFR mutational analysis for patients with NSCLC carcinoma.

Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non–Small-Cell Lung Cancer

2010 ◽  
Vol 28 (18) ◽  
pp. 3076-3083 ◽  
Author(s):  
Lecia V. Sequist ◽  
Benjamin Besse ◽  
Thomas J. Lynch ◽  
Vincent A. Miller ◽  
Kwok K. Wong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Egfr Mutation ◽  
Objective Response ◽  
Resistance Mutation ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung

PurposeEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have had a significant impact on non–small-cell lung cancer (NSCLC) outcomes, particularly for patients with EGFR mutations. Resistance emerges after 9 to 12 months, primarily mediated by the T790M resistance mutation. We studied neratinib, an irreversible pan-ErbB TKI that may overcome T790M.Patients and MethodsPatients with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with ≥ 12 weeks of prior TKI therapy were placed in arm A if they were EGFR mutation positive or arm B if they were wild-type. Arm C included TKI-naïve patients with adenocarcinoma and light smoking histories (≤ 20 pack-years). All patients received daily oral neratinib, initially at 320 mg but subsequently reduced to 240 mg because of excessive diarrhea. The primary end point was objective response rate (RR).ResultsOne-hundred sixty-seven patients were treated: 91 in arm A, 48 in arm B, and 28 in arm C. Diarrhea was the most common toxicity; grade 3 incidence was 50% at 320 mg but improved to 25% after dose reduction. The RR was 3% in arm A and zero in arms B and C. No patients with known T790M responded. Notably, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks.ConclusionNeratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.

Mutations in the tyrosine kinase domain of the EGFR gene associated with gefitinib response in non-small-cell lung cancer

Lung Cancer ◽  
2005 ◽  
Vol 50 (1) ◽  
pp. 25-33 ◽  
Author(s):  
Rafael Rosell ◽  
Yukito Ichinose ◽  
Miquel Taron ◽  
Carme Sarries ◽  
Cristina Queralt ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Domain ◽  
Small Cell ◽  
Tyrosine Kinase Domain ◽  
Small Cell Lung ◽  
Egfr Gene

ERCC1 expression by immunohistochemistry and EGFR mutations in resected non-small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7646-7646 ◽  
Author(s):  
K. Lee ◽  
S. Han ◽  
H. Min ◽  
D. Oh ◽  
S. Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Excision Repair ◽  
Direct Sequencing ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Ercc1 Expression

7646 Background: To investigate whether excision repair cross-complementation group 1 (ERCC1) expression, as determined immunohistochemically, and mutations of epidermal growth factor receptor (EGFR) are related to the prognosis of curatively resected non-small cell lung cancer (NSCLC), and whether these two markers are related. Methods: One-hundred and thirty-three consecutive patients with NSCLC who did not receive adjuvant chemotherapy after curative surgery were included in this study. Representative areas from formalin-fixed paraffin-embedded tumor samples were chosen for tissue microarray analysis. Immunohistochemistry was performed for ERCC1 and the median semiquantitative H-score was used as a cut-off. EGFR mutations (exons 18, 19, and 21) were analyzed by the direct sequencing of tumor samples. Results: ERCC1 expression was evaluable in 130 patients and ERCC1 was found to be positive in 80 patients (61.5%). Moreover, ERCC1 was expressed more frequently in smokers and in squamous cell carcinomas. Patients with positive ERCC1 expression survived longer (median overall survival 2,742 days for ERCC1-positive vs. 1,423 days for ERCC1-negative, P=.0463). EGFR mutations were found in 27 patients (20.3%) but they were not found to affect overall survival. Interestingly, EGFR mutations were more frequent in ERCC1-negative tumors (12.5% in ERCC1-positive vs. 30% in ERCC1-negative tumors, P=0.014). Conclusions: ERCC1 expression was identified as a prognostic marker of longer survival in resected NSCLCs. In addition, EGFR mutations were more frequently found in ERCC1-negative tumors, but were not found to affect survival in our patient group. No significant financial relationships to disclose.

scholarly journals Integrated Omics Analysis of Non-Small-Cell Lung Cancer Cells Harboring the EGFR C797S Mutation Reveals the Potential of AXL as a Novel Therapeutic Target in TKI-Resistant Lung Cancer

Cancers ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 111
Author(s):  
Tong-Hong Wang ◽  
Chih-Ching Wu ◽  
Kuo-Yen Huang ◽  
Yann-Lii Leu ◽  
Shuenn-Chen Yang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Cell Model ◽  
Small Cell ◽  
Egfr Mutations ◽  
Nsclc Cell Line ◽  
Small Cell Lung

Oncogenic mutations of epidermal growth factor receptor (EGFR) are responsive to targeted tyrosine kinase inhibitor (TKI) treatment in non-small-cell lung cancer (NSCLC). However, NSCLC patients harboring activating EGFR mutations inevitably develop resistance to TKIs. The acquired EGFR C797S mutation is a known mechanism that confers resistance to third-generation EGFR TKIs such as AZD9291. In this work, we employed CRISPR/Cas9 genome-editing technology to knock-in the EGFR C797S mutation into an NSCLC cell line harboring EGFR L858R/T790M. The established cell model was used to investigate the biology and treatment strategy of acquired EGFR C797S mutations. Transcriptome and proteome analyses revealed that the differentially expressed genes/proteins in the cells harboring the EGFR C797S mutation are associated with a mesenchymal-like cell state with elevated expression of AXL receptor tyrosine kinase. Furthermore, we presented evidence that inhibition of AXL is effective in slowing the growth of NSCLC cells harboring EGFR C797S. Our findings suggest that AXL inhibition could be a second-line or a potential adjuvant treatment for NSCLC harboring the EGFR C797S mutation.

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