scholarly journals Growth Suppression in Lung Cancer Cells Harboring EGFR-C797S Mutation by Quercetin

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1271
Author(s):  
Kuo-Yen Huang ◽  
Tong-Hong Wang ◽  
Chin-Chuan Chen ◽  
Yann-Lii Leu ◽  
Hsin-Jung Li ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tumor Growth ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Egfr Mutations ◽  
Third Generation ◽  
Small Cell Lung ◽  
Cytotoxic Effects

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approved treatments for non-small-cell lung cancer (NSCLC) patients harboring activating EGFR mutations. The EGFR C797S mutation is one of the known acquired-resistance mutations to the latest third-generation TKIs. At present, there are no clear options for treating patients who acquire resistance to third-generation TKIs. The acquisition of the EGFR C797S mutation was shown to upregulate the expression of AXL, a receptor tyrosine kinase of the TAM (TYRO3-AXL-MER) family, and the suppression of AXL is effective in reducing the growth of NSCLC cells harboring EGFR C797S. As quercetin was recently shown to inhibit AXL, quercetin may be effective in treating NSCLC cells harboring the EGFR C797S mutation. In this work, the cytotoxic effects of quercetin and its ability to inhibit tumor growth were examined in TKI-resistant NSCLC cells harboring the EGFR C797S mutation. We demonstrated that quercetin exhibited potent cytotoxic effects on NSCLC cells harboring the EGFR C797S mutation by inhibiting AXL and inducing apoptosis. Quercetin inhibited the tumor growth of xenografted NSCLC cells harboring the EGFR C797S mutation and appeared to act synergistically with brigatinib to inhibit of tumor growth in vivo. In summary, herein, we revealed that quercetin is an effective inhibitor for the treatment of non-small-cell lung cancer harboring the EGFR C797S mutation.

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.

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.

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.

Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy

2020 ◽  
Vol 27 (32) ◽  
pp. 5274-5316 ◽  
Author(s):  
Sitanshu S. Singh ◽  
Achyut Dahal ◽  
Leeza Shrestha ◽  
Seetharama D. Jois
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Relative Survival ◽  
Small Cell ◽  
Egfr Mutations ◽  
Cancer Resistance ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma

Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.

scholarly journals Non-invasive detection of EGFR mutations by cell-free loop-mediated isothermal amplification (CF-LAMP)

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Srividya Arjuna ◽  
Rajesh Venkataram ◽  
Pandyanda Nanjappa Dechamma ◽  
Gunimala Chakraborty ◽  
Nishith Babu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Lamp Assay ◽  
Cost Effective ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Non Invasive

Abstract Targeting epidermal growth factor receptor (EGFR) through tyrosine kinase inhibitors (TKI) is a successful therapeutic strategy in non-small cell lung cancer. However, the response to TKI therapy depends on specific activating and acquired mutations in the tyrosine kinase domain of the EGFR gene. Therefore, confirming the EGFR status of patients is crucial, not only for determining the eligibility, but also for monitoring the emergence of mutations in patients under TKI therapy. In this study, our aim was to develop a cost effective, yet sensitive, technique that allows the detection of therapeutically-relevant EGFR hotspot mutations at isothermal conditions in a non-invasive manner. Previously, we developed an allele-specific loop-mediated isothermal amplification (AS-LAMP) assay for screening germline and somatic de novo T790M EGFR mutation in lung cancer patients. In this study, we used cell free DNA as a template in AS-LAMP assay (CF-LAMP) for non-invasive detection of two hotspot EGFR mutations (T790M, and L858R) and compared its efficiency with ultrasensitive droplet digital PCR (ddPCR) assay. The results of CF-LAMP assay were consistent with those obtained in ddPCR assay, indicating the robustness of the method. CF-LAMP may serve as a valuable and cost-effective alternative for liquid biopsy techniques used in molecular diagnosis of non-small cell lung cancer.

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