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

Yi Hung Carol Tan, Tamara Mirzapoiazova, Brian M. Won, Li Zhu, Minu K. Srivastava, Everett E. Vokes, Aliya N. Husain, Surinder Kumar Batra, Sherven Sharma, Ravi Salgia

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number9192
JournalScientific reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Non-Small Cell Lung Carcinoma
Lymphoma
Paxillin
Ubiquitin-Protein Ligases
Ubiquitination
Cell Movement
Phosphorylation
RNA
Cell Line

ASJC Scopus subject areas

  • General

Cite this

Tan, Y. H. C., Mirzapoiazova, T., Won, B. M., Zhu, L., Srivastava, M. K., Vokes, E. E., ... Salgia, R. (2017). Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL. Scientific reports, 7(1), [9192]. https://doi.org/10.1038/s41598-017-09078-4

Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL. / Tan, Yi Hung Carol; Mirzapoiazova, Tamara; Won, Brian M.; Zhu, Li; Srivastava, Minu K.; Vokes, Everett E.; Husain, Aliya N.; Batra, Surinder Kumar; Sharma, Sherven; Salgia, Ravi.

In: Scientific reports, Vol. 7, No. 1, 9192, 01.12.2017.

Research output: Contribution to journalArticle

Tan, YHC, Mirzapoiazova, T, Won, BM, Zhu, L, Srivastava, MK, Vokes, EE, Husain, AN, Batra, SK, Sharma, S & Salgia, R 2017, 'Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL', Scientific reports, vol. 7, no. 1, 9192. https://doi.org/10.1038/s41598-017-09078-4
Tan, Yi Hung Carol ; Mirzapoiazova, Tamara ; Won, Brian M. ; Zhu, Li ; Srivastava, Minu K. ; Vokes, Everett E. ; Husain, Aliya N. ; Batra, Surinder Kumar ; Sharma, Sherven ; Salgia, Ravi. / Differential responsiveness of MET inhibition in non-small-cell lung cancer with altered CBL. In: Scientific reports. 2017 ; Vol. 7, No. 1.
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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.",
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