Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

Abstract Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and se...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Ikuko Takeda Nakamura, Shinji Kohsaka, Masachika Ikegami, Hiroshi Ikeuchi, Toshihide Ueno, Kunhua Li, Tyler S. Beyett, Takafumi Koyama, Toshio Shimizu, Noboru Yamamoto, Fumiyuki Takahashi, Kazuhisa Takahashi, Michael J. Eck, Hiroyuki Mano
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/1eb0d4f54965435d896fb494c2235251
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1eb0d4f54965435d896fb494c2235251
record_format	dspace
spelling	oai:doaj.org-article:1eb0d4f54965435d896fb494c22352512021-12-02T16:14:15ZComprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer10.1038/s41698-021-00204-02397-768Xhttps://doaj.org/article/1eb0d4f54965435d896fb494c22352512021-07-01T00:00:00Zhttps://doi.org/10.1038/s41698-021-00204-0https://doaj.org/toc/2397-768XAbstract Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.Ikuko Takeda NakamuraShinji KohsakaMasachika IkegamiHiroshi IkeuchiToshihide UenoKunhua LiTyler S. BeyettTakafumi KoyamaToshio ShimizuNoboru YamamotoFumiyuki TakahashiKazuhisa TakahashiMichael J. EckHiroyuki ManoNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Precision Oncology, Vol 5, Iss 1, Pp 1-14 (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 Ikuko Takeda Nakamura Shinji Kohsaka Masachika Ikegami Hiroshi Ikeuchi Toshihide Ueno Kunhua Li Tyler S. Beyett Takafumi Koyama Toshio Shimizu Noboru Yamamoto Fumiyuki Takahashi Kazuhisa Takahashi Michael J. Eck Hiroyuki Mano Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
description	Abstract Various genetic alterations of the fibroblast growth factor receptor (FGFR) family have been detected across a wide range of cancers. However, inhibition of FGFR signaling by kinase inhibitors demonstrated limited clinical effectiveness. Herein, we evaluated the transforming activity and sensitivity of 160 nonsynonymous FGFR mutations and ten fusion genes to seven FGFR tyrosine kinase inhibitors (TKI) using the mixed-all-nominated-in-one (MANO) method, a high-throughput functional assay. The oncogenicity of 71 mutants was newly discovered in this study. The FGFR TKIs showed anti-proliferative activities against the wild-type FGFRs and their fusions, while several hotspot mutants were relatively resistant to those TKIs. The drug sensitivities assessed with the MANO method were well concordant with those evaluated using in vitro and in vivo assays. Comprehensive analysis of published FGFR structures revealed a possible mechanism through which oncogenic FGFR mutations reduce sensitivity to TKIs. It was further revealed that recurrent compound mutations within FGFRs affect the transforming potential and TKI-sensitivity of corresponding kinases. In conclusion, our study suggests the importance of selecting suitable inhibitors against individual FGFR variants. Moreover, it reveals the necessity to develop next-generation FGFR inhibitors, which are effective against all oncogenic FGFR variants.
format	article
author	Ikuko Takeda Nakamura Shinji Kohsaka Masachika Ikegami Hiroshi Ikeuchi Toshihide Ueno Kunhua Li Tyler S. Beyett Takafumi Koyama Toshio Shimizu Noboru Yamamoto Fumiyuki Takahashi Kazuhisa Takahashi Michael J. Eck Hiroyuki Mano
author_facet	Ikuko Takeda Nakamura Shinji Kohsaka Masachika Ikegami Hiroshi Ikeuchi Toshihide Ueno Kunhua Li Tyler S. Beyett Takafumi Koyama Toshio Shimizu Noboru Yamamoto Fumiyuki Takahashi Kazuhisa Takahashi Michael J. Eck Hiroyuki Mano
author_sort	Ikuko Takeda Nakamura
title	Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
title_short	Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
title_full	Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
title_fullStr	Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
title_full_unstemmed	Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
title_sort	comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1eb0d4f54965435d896fb494c2235251
work_keys_str_mv	AT ikukotakedanakamura comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT shinjikohsaka comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT masachikaikegami comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT hiroshiikeuchi comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT toshihideueno comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT kunhuali comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT tylersbeyett comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT takafumikoyama comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT toshioshimizu comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT noboruyamamoto comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT fumiyukitakahashi comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT kazuhisatakahashi comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT michaeljeck comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer AT hiroyukimano comprehensivefunctionalevaluationofvariantsoffibroblastgrowthfactorreceptorgenesincancer
_version_	1718384338114969600

Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer

Ejemplares similares