Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer

Harrison, Peter T.; Vyse, Simon; Huang, Paul H.

doi:10.1016/j.semcancer.2019.09.015

Cited by 413 publications

(326 citation statements)

References 102 publications

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“…L858R is one of the most common activating mutations that confers sensitivity to TKI and accounts for about 41% of observed EGFR mutations in NSCLC 18 . In our study, we observed a staggering 89% of the cases to be positive for this mutation.…”

Section: Discussionmentioning

confidence: 99%

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

Arjuna

Venkataram

Dechamma

et al. 2020

Sci Rep

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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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Section: Discussionmentioning

confidence: 99%

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

Arjuna

Venkataram

Dechamma

et al. 2020

Sci Rep

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“…We found that the 1NME, a crystal structure of target CASP3 could have intense interaction with compound Acacetin. EGFR mutation played a major role in the carcinogenesis of NSCL [50,51] . EGFR could be transactivated by PAR2 receptor to achieve the transfer activity of A549 cells [52] .…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology Revealed the mechanism of Platycodon grandiflorum in Lung Cancer Treatment

Chen

Zhang

Wang

et al. 2020

Preprint

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Background: Traditional Chinese Medicine has demonstrated increasingly unique advantages in the treatment of lung cancer. Through literature review, it was found out that Platycodon grandiflorum had immunomodulatory and anti-inflammatory effects, and it had a special targeting effect on the lung. Purpose：In order to determine the molecular mechanism of Platycodon grandiflorum in lung cancer treatment. Network pharmacology theory was used to do a systematic study.Methods: The active compounds of Platycodon grandiflorum were screened from TCMSP database. Then, compounds targets were predicted with the assistance of Swiss Target Prediction and STITCH. The targets of lung cancer were screened form TTD and DisGeNET database. The common targets of compounds and lung cancer were screened out for following analysis. A Protein-Protein Interaction (PPI) Network was constructed by STRING. Subsequent to topological analysis, the hub targets were screened out for KEGG pathway and GO Enrichment. Molecular docking by AutoVina was performed to investigate the binding ability between the hub targets and compounds. Results: There were 4 active compounds screened out, including Acacetin, Spinasterol, cis-Dihydroquercetin and Luteolin. There were 80 targets screened as the common target of compounds and lung cancer. After topological analysis TP53, AKT1, VEGFA, CASP3, IL6, EGFR and MAPK1 were identified as hub targets. The 7 hub targets might be involved in 81 biological annotation and in the regulation of 23 pathways to intervene lung cancer. The main functional annotation was negative regulation of apoptotic process. Almost all of the pathways were directly or indirectly associated with the PI3K-Akt signal pathway and MAPK signal pathway. According to Affinity score of molecular docking the best binding protein for Luteolin was EGFR, and the best binding protein for Acacetin was CASP3. This meant that the Platycodon grandiflorum was easier to combine these two targets than other targets.Conclusion: Our study affirmed the effectiveness of Platycodon grandiflorum in treatment of lung cancer from molecular level. And we found that EGFR and CASP3 were the most likely targets for the direct action of Platycodon grandiflorum. The most important pathways that Platycodon grandiflori might interfere with were PI3K-Akt signaling pathway and MAPK signaling pathway.

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“…Combination therapy/polytherapy is a promising approach for treating lung cancer and abrogating the outgrowth of resistance-causing mutant subpopulations [30]. However, the use of appropriate polytherapies is impeded by the difficulty associated with investigating the efficacy of large numbers of possible drug combinations, given that mutation in multiple genes can drive lung cancer and multiple drugs may be needed to target multiple impacted pathways.…”

Section: Introductionmentioning

confidence: 99%

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

et al. 2020

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A model that recapitulates development of acquired therapeutic resistance is needed to improve oncology drug development and patient outcomes. To achieve this end, we established methods for the preparation and growth of spheroids from primary human lung adenocarcinomas, including methods to culture, passage, monitor growth, and evaluate changes in mutational profile over time. Primary lung tumor spheroids were cultured in Matrigel ® with varying concentrations of erlotinib, a small molecule kinase inhibitor of epidermal growth factor receptor (EGFR) that is ineffective against KRAS mutant cells. Subtle changes in spheroid size and number were observed within the first two weeks of culture. Spheroids were cultured for up to 24 weeks, during which time interactions between different cell types, movement, and assembly into heterogeneous organoid structures were documented. Allele-specific competitive blocker PCR (ACB-PCR) was used to quantify low frequency BRAF V600E, KRAS G12D, KRAS G12V, and PIK3CA H1047R mutant subpopulations in tumor tissue residue (TR) samples and cultured spheroids. Mutant subpopulations, including multiple mutant subpopulations, were quite prevalent. Twelve examples of mutant enrichment were found in eight of the 14 tumors analyzed, based on the criteria that a statistically-significant increase in mutant fraction was observed relative to both the TR and the no-erlotinib control. Of the mutants quantified in erlotinib-treated cultures, PIK3CA H1047 mutant subpopulations increased most often (5/14 tumors), which is consistent with clinical observations. Thus, this ex vivo lung tumor spheroid model replicates the cellular and mutational tumor heterogeneity of human lung adenocarcinomas and can be used to assess the outgrowth of mutant subpopulations. Spheroid cultures with characterized mutant subpopulations could be used to investigate the efficacy of lung cancer combination therapies.

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Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer

Cited by 413 publications

References 102 publications

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

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

Network Pharmacology Revealed the mechanism of Platycodon grandiflorum in Lung Cancer Treatment

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

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