Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity

Abstract Approximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding th...

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Autores principales:	Takahiro Yoshizawa, Ken Uchibori, Mitsugu Araki, Shigeyuki Matsumoto, Biao Ma, Ryo Kanada, Yosuke Seto, Tomoko Oh-hara, Sumie Koike, Ryo Ariyasu, Satoru Kitazono, Hironori Ninomiya, Kengo Takeuchi, Noriko Yanagitani, Satoshi Takagi, Kazuma Kishi, Naoya Fujita, Yasushi Okuno, Makoto Nishio, Ryohei Katayama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/c1c4f342481c4dad8da1ff3a202ae813
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spelling	oai:doaj.org-article:c1c4f342481c4dad8da1ff3a202ae8132021-12-02T18:03:30ZMicrosecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity10.1038/s41698-021-00170-72397-768Xhttps://doaj.org/article/c1c4f342481c4dad8da1ff3a202ae8132021-04-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00170-7https://doaj.org/toc/2397-768XAbstract Approximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.Takahiro YoshizawaKen UchiboriMitsugu ArakiShigeyuki MatsumotoBiao MaRyo KanadaYosuke SetoTomoko Oh-haraSumie KoikeRyo AriyasuSatoru KitazonoHironori NinomiyaKengo TakeuchiNoriko YanagitaniSatoshi TakagiKazuma KishiNaoya FujitaYasushi OkunoMakoto NishioRyohei KatayamaNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Takahiro Yoshizawa Ken Uchibori Mitsugu Araki Shigeyuki Matsumoto Biao Ma Ryo Kanada Yosuke Seto Tomoko Oh-hara Sumie Koike Ryo Ariyasu Satoru Kitazono Hironori Ninomiya Kengo Takeuchi Noriko Yanagitani Satoshi Takagi Kazuma Kishi Naoya Fujita Yasushi Okuno Makoto Nishio Ryohei Katayama Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
description	Abstract Approximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.
format	article
author	Takahiro Yoshizawa Ken Uchibori Mitsugu Araki Shigeyuki Matsumoto Biao Ma Ryo Kanada Yosuke Seto Tomoko Oh-hara Sumie Koike Ryo Ariyasu Satoru Kitazono Hironori Ninomiya Kengo Takeuchi Noriko Yanagitani Satoshi Takagi Kazuma Kishi Naoya Fujita Yasushi Okuno Makoto Nishio Ryohei Katayama
author_facet	Takahiro Yoshizawa Ken Uchibori Mitsugu Araki Shigeyuki Matsumoto Biao Ma Ryo Kanada Yosuke Seto Tomoko Oh-hara Sumie Koike Ryo Ariyasu Satoru Kitazono Hironori Ninomiya Kengo Takeuchi Noriko Yanagitani Satoshi Takagi Kazuma Kishi Naoya Fujita Yasushi Okuno Makoto Nishio Ryohei Katayama
author_sort	Takahiro Yoshizawa
title	Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
title_short	Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
title_full	Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
title_fullStr	Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
title_full_unstemmed	Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity
title_sort	microsecond-timescale md simulation of egfr minor mutation predicts the structural flexibility of egfr kinase core that reflects egfr inhibitor sensitivity
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c1c4f342481c4dad8da1ff3a202ae813
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Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity

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