Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations

Abstract Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are...

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Autores principales:	Bin Zou, Victor H. F. Lee, Lijiang Chen, Lichun Ma, Debby D. Wang, Hong Yan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e
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spelling	oai:doaj.org-article:48baaceb101f44bbbb0e692bec36675e2021-12-02T16:06:16ZDeciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations10.1038/s41598-017-06632-y2045-2322https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06632-yhttps://doaj.org/toc/2045-2322Abstract Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy. Liquid biopsy after progression to their last line of systemic therapy were taken for detection of acquired T790M mutation. By performing attribute ranking we found that several attributes, including the initial EGFR mutational type, had a high correlation with the presence of acquired T790M mutation. We also conducted computational studies and discovered that the EGFR mutation delE746_A750 had a lower stability around the residue T790 than delS752_I759 and L858R, which was consistent with our clinical observation that patients with delE746_A750 were more likely to acquire T790M mutation than those with delS752_I759 or L858R. Our results provided new insight to future direction of research on investigating the mechanisms of acquired T790M mutation, which is essential to the development of novel mutation-specific TKIs.Bin ZouVictor H. F. LeeLijiang ChenLichun MaDebby D. WangHong YanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Bin Zou Victor H. F. Lee Lijiang Chen Lichun Ma Debby D. Wang Hong Yan Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
description	Abstract Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy. Liquid biopsy after progression to their last line of systemic therapy were taken for detection of acquired T790M mutation. By performing attribute ranking we found that several attributes, including the initial EGFR mutational type, had a high correlation with the presence of acquired T790M mutation. We also conducted computational studies and discovered that the EGFR mutation delE746_A750 had a lower stability around the residue T790 than delS752_I759 and L858R, which was consistent with our clinical observation that patients with delE746_A750 were more likely to acquire T790M mutation than those with delS752_I759 or L858R. Our results provided new insight to future direction of research on investigating the mechanisms of acquired T790M mutation, which is essential to the development of novel mutation-specific TKIs.
format	article
author	Bin Zou Victor H. F. Lee Lijiang Chen Lichun Ma Debby D. Wang Hong Yan
author_facet	Bin Zou Victor H. F. Lee Lijiang Chen Lichun Ma Debby D. Wang Hong Yan
author_sort	Bin Zou
title	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
title_short	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
title_full	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
title_fullStr	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
title_full_unstemmed	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
title_sort	deciphering mechanisms of acquired t790m mutation after egfr inhibitors for nsclc by computational simulations
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e
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Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations

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