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...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Bin Zou [verfasserIn] Victor H. F. Lee [verfasserIn] Lijiang Chen [verfasserIn] Lichun Ma [verfasserIn] Debby D. Wang [verfasserIn] Hong Yan [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Übergeordnetes Werk:	In: Scientific Reports - Nature Portfolio, 2011, 7(2017), 1, Seite 13
Übergeordnetes Werk:	volume:7 ; year:2017 ; number:1 ; pages:13

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41598-017-06632-y

Katalog-ID:	DOAJ063411318

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allfields	10.1038/s41598-017-06632-y doi (DE-627)DOAJ063411318 (DE-599)DOAJ48baaceb101f44bbbb0e692bec36675e DE-627 ger DE-627 rakwb eng Bin Zou verfasserin aut Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Victor H. F. Lee verfasserin aut Lijiang Chen verfasserin aut Lichun Ma verfasserin aut Debby D. Wang verfasserin aut Hong Yan verfasserin aut In Scientific Reports Nature Portfolio, 2011 7(2017), 1, Seite 13 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:7 year:2017 number:1 pages:13 https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e kostenfrei https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2017 1 13
spelling	10.1038/s41598-017-06632-y doi (DE-627)DOAJ063411318 (DE-599)DOAJ48baaceb101f44bbbb0e692bec36675e DE-627 ger DE-627 rakwb eng Bin Zou verfasserin aut Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Victor H. F. Lee verfasserin aut Lijiang Chen verfasserin aut Lichun Ma verfasserin aut Debby D. Wang verfasserin aut Hong Yan verfasserin aut In Scientific Reports Nature Portfolio, 2011 7(2017), 1, Seite 13 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:7 year:2017 number:1 pages:13 https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e kostenfrei https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2017 1 13
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allfieldsGer	10.1038/s41598-017-06632-y doi (DE-627)DOAJ063411318 (DE-599)DOAJ48baaceb101f44bbbb0e692bec36675e DE-627 ger DE-627 rakwb eng Bin Zou verfasserin aut Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Victor H. F. Lee verfasserin aut Lijiang Chen verfasserin aut Lichun Ma verfasserin aut Debby D. Wang verfasserin aut Hong Yan verfasserin aut In Scientific Reports Nature Portfolio, 2011 7(2017), 1, Seite 13 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:7 year:2017 number:1 pages:13 https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e kostenfrei https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2017 1 13
allfieldsSound	10.1038/s41598-017-06632-y doi (DE-627)DOAJ063411318 (DE-599)DOAJ48baaceb101f44bbbb0e692bec36675e DE-627 ger DE-627 rakwb eng Bin Zou verfasserin aut Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier 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. Medicine R Science Q Victor H. F. Lee verfasserin aut Lijiang Chen verfasserin aut Lichun Ma verfasserin aut Debby D. Wang verfasserin aut Hong Yan verfasserin aut In Scientific Reports Nature Portfolio, 2011 7(2017), 1, Seite 13 (DE-627)663366712 (DE-600)2615211-3 20452322 nnns volume:7 year:2017 number:1 pages:13 https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e kostenfrei https://doi.org/10.1038/s41598-017-06632-y kostenfrei https://doaj.org/toc/2045-2322 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_381 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2017 1 13
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author	Bin Zou
spellingShingle	Bin Zou misc Medicine misc R misc Science misc Q Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
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topic_title	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
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title	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
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title_full	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
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title_sort	deciphering mechanisms of acquired t790m mutation after egfr inhibitors for nsclc by computational simulations
title_auth	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
abstract	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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
url	https://doi.org/10.1038/s41598-017-06632-y https://doaj.org/article/48baaceb101f44bbbb0e692bec36675e https://doaj.org/toc/2045-2322
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