Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity an...

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Autores principales:	Long-Sheng Chang, Janet L Oblinger, Abbi E Smith, Marc Ferrer, Steven P Angus, Eric Hawley, Alejandra M Petrilli, Roberta L Beauchamp, Lars Björn Riecken, Serkan Erdin, Ming Poi, Jie Huang, Waylan K Bessler, Xiaohu Zhang, Rajarshi Guha, Craig Thomas, Sarah S Burns, Thomas S K Gilbert, Li Jiang, Xiaohong Li, Qingbo Lu, Jin Yuan, Yongzheng He, Shelley A H Dixon, Andrea Masters, David R Jones, Charles W Yates, Stephen J Haggarty, Salvatore La Rosa, D Bradley Welling, Anat O Stemmer-Rachamimov, Scott R Plotkin, James F Gusella, Justin Guinney, Helen Morrison, Vijaya Ramesh, Cristina Fernandez-Valle, Gary L Johnson, Jaishri O Blakeley, D Wade Clapp, Synodos for NF2 Consortium
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d5cdd322a442449ebaffcbfad82ea6a3
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spelling	oai:doaj.org-article:d5cdd322a442449ebaffcbfad82ea6a32021-12-02T20:05:02ZBrigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.1932-620310.1371/journal.pone.0252048https://doaj.org/article/d5cdd322a442449ebaffcbfad82ea6a32021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252048https://doaj.org/toc/1932-6203Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.Long-Sheng ChangJanet L OblingerAbbi E SmithMarc FerrerSteven P AngusEric HawleyAlejandra M PetrilliRoberta L BeauchampLars Björn RieckenSerkan ErdinMing PoiJie HuangWaylan K BesslerXiaohu ZhangRajarshi GuhaCraig ThomasSarah S BurnsThomas S K GilbertLi JiangXiaohong LiQingbo LuJin YuanYongzheng HeShelley A H DixonAndrea MastersDavid R JonesCharles W YatesStephen J HaggartySalvatore La RosaD Bradley WellingAnat O Stemmer-RachamimovScott R PlotkinJames F GusellaJustin GuinneyHelen MorrisonVijaya RameshCristina Fernandez-ValleGary L JohnsonJaishri O BlakeleyD Wade ClappSynodos for NF2 ConsortiumPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0252048 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Long-Sheng Chang Janet L Oblinger Abbi E Smith Marc Ferrer Steven P Angus Eric Hawley Alejandra M Petrilli Roberta L Beauchamp Lars Björn Riecken Serkan Erdin Ming Poi Jie Huang Waylan K Bessler Xiaohu Zhang Rajarshi Guha Craig Thomas Sarah S Burns Thomas S K Gilbert Li Jiang Xiaohong Li Qingbo Lu Jin Yuan Yongzheng He Shelley A H Dixon Andrea Masters David R Jones Charles W Yates Stephen J Haggarty Salvatore La Rosa D Bradley Welling Anat O Stemmer-Rachamimov Scott R Plotkin James F Gusella Justin Guinney Helen Morrison Vijaya Ramesh Cristina Fernandez-Valle Gary L Johnson Jaishri O Blakeley D Wade Clapp Synodos for NF2 Consortium Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
description	Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.
format	article
author	Long-Sheng Chang Janet L Oblinger Abbi E Smith Marc Ferrer Steven P Angus Eric Hawley Alejandra M Petrilli Roberta L Beauchamp Lars Björn Riecken Serkan Erdin Ming Poi Jie Huang Waylan K Bessler Xiaohu Zhang Rajarshi Guha Craig Thomas Sarah S Burns Thomas S K Gilbert Li Jiang Xiaohong Li Qingbo Lu Jin Yuan Yongzheng He Shelley A H Dixon Andrea Masters David R Jones Charles W Yates Stephen J Haggarty Salvatore La Rosa D Bradley Welling Anat O Stemmer-Rachamimov Scott R Plotkin James F Gusella Justin Guinney Helen Morrison Vijaya Ramesh Cristina Fernandez-Valle Gary L Johnson Jaishri O Blakeley D Wade Clapp Synodos for NF2 Consortium
author_facet	Long-Sheng Chang Janet L Oblinger Abbi E Smith Marc Ferrer Steven P Angus Eric Hawley Alejandra M Petrilli Roberta L Beauchamp Lars Björn Riecken Serkan Erdin Ming Poi Jie Huang Waylan K Bessler Xiaohu Zhang Rajarshi Guha Craig Thomas Sarah S Burns Thomas S K Gilbert Li Jiang Xiaohong Li Qingbo Lu Jin Yuan Yongzheng He Shelley A H Dixon Andrea Masters David R Jones Charles W Yates Stephen J Haggarty Salvatore La Rosa D Bradley Welling Anat O Stemmer-Rachamimov Scott R Plotkin James F Gusella Justin Guinney Helen Morrison Vijaya Ramesh Cristina Fernandez-Valle Gary L Johnson Jaishri O Blakeley D Wade Clapp Synodos for NF2 Consortium
author_sort	Long-Sheng Chang
title	Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
title_short	Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
title_full	Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
title_fullStr	Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
title_full_unstemmed	Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.
title_sort	brigatinib causes tumor shrinkage in both nf2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not alk.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/d5cdd322a442449ebaffcbfad82ea6a3
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Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

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