Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL

Abstract Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expre...

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Autores principales:	Yi-Hung Carol Tan, Tamara Mirzapoiazova, Brian M. Won, Li Zhu, Minu K. Srivastava, Everett E. Vokes, Aliya N. Husain, Surinder K. Batra, Sherven Sharma, Ravi Salgia
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/16f501031f654eb7b913e9777d40b719
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spelling	oai:doaj.org-article:16f501031f654eb7b913e9777d40b7192021-12-02T15:06:02ZDifferential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL10.1038/s41598-017-09078-42045-2322https://doaj.org/article/16f501031f654eb7b913e9777d40b7192017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-09078-4https://doaj.org/toc/2045-2322Abstract Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expression than CBL mutant cells. Ubiquitination of MET was also decreased in CBL mutant cells compared to wildtype cells. Mutant cells were also more sensitive to MET inhibitor SU11274 than wild-type cells. sh-RNA-mediated knockdown of CBL enhanced cell motility and colony formation in NSCLC cells, and these activities were inhibited by SU11274. Assessment of the phospho-kinome showed decreased phosphorylation of pathways involving MET, paxillin, EPHA2, and VEGFR. When CBL was knocked down in the mutant cell line H1975 (erlotinib-resistant), it became sensitive to MET inhibition. Our findings suggest that CBL status is a potential positive indicator for MET-targeted therapeutics in NSCLC.Yi-Hung Carol TanTamara MirzapoiazovaBrian M. WonLi ZhuMinu K. SrivastavaEverett E. VokesAliya N. HusainSurinder K. BatraSherven SharmaRavi SalgiaNature 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 Yi-Hung Carol Tan Tamara Mirzapoiazova Brian M. Won Li Zhu Minu K. Srivastava Everett E. Vokes Aliya N. Husain Surinder K. Batra Sherven Sharma Ravi Salgia Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
description	Abstract Casitas B-lineage lymphoma (CBL) is an E3 ubiquitin ligase and a molecule of adaptor that we have shown is important for non-small-cell lung cancer (NSCLC). We investigated if MET is a target of CBL and if enhanced in CBL-altered NSCLC. We showed that CBL wildtype cells have lower MET expression than CBL mutant cells. Ubiquitination of MET was also decreased in CBL mutant cells compared to wildtype cells. Mutant cells were also more sensitive to MET inhibitor SU11274 than wild-type cells. sh-RNA-mediated knockdown of CBL enhanced cell motility and colony formation in NSCLC cells, and these activities were inhibited by SU11274. Assessment of the phospho-kinome showed decreased phosphorylation of pathways involving MET, paxillin, EPHA2, and VEGFR. When CBL was knocked down in the mutant cell line H1975 (erlotinib-resistant), it became sensitive to MET inhibition. Our findings suggest that CBL status is a potential positive indicator for MET-targeted therapeutics in NSCLC.
format	article
author	Yi-Hung Carol Tan Tamara Mirzapoiazova Brian M. Won Li Zhu Minu K. Srivastava Everett E. Vokes Aliya N. Husain Surinder K. Batra Sherven Sharma Ravi Salgia
author_facet	Yi-Hung Carol Tan Tamara Mirzapoiazova Brian M. Won Li Zhu Minu K. Srivastava Everett E. Vokes Aliya N. Husain Surinder K. Batra Sherven Sharma Ravi Salgia
author_sort	Yi-Hung Carol Tan
title	Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
title_short	Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
title_full	Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
title_fullStr	Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
title_full_unstemmed	Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL
title_sort	differential responsiveness of met inhibition in non-small-cell lung cancer with altered cbl
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/16f501031f654eb7b913e9777d40b719
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Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL

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