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Sci Rep. 2017 Aug 23;7(1):9192. doi: 10.1038/s41598-017-09078-4.

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

Author information

1
Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine and Biologic Sciences, Chicago, IL, USA.
2
Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA, USA.
3
Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
4
Department of Pathology, The University of Chicago Medicine and Biologic Sciences, Chicago, IL, USA.
5
Department of Biochemistry and Molecular Biology, University of Nebraska College of Medicine, Omaha, NE, USA.
6
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
7
Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA, USA. rsalgia@coh.org.

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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