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.
Highlights
Lung cancer is the second most common cancer in both men and women, and it has a very poor prognosis[1]
Many studies have indicated that CBL (Casitas B-lineage lymphoma) plays an important role in down-regulating Receptor tyrosine kinases (RTKs) based on its E3 ubiquitin ligase activity[8, 9]
Mutations in CBL were first reported in human acute myeloid leukemia (AML), and over the past several years, CBL mutations have been identified in other types of leukemia[11, 12]
Summary
Lung cancer is the second most common cancer in both men and women, and it has a very poor prognosis[1]. Our previous studies were the first to report CBL mutations in solid tumors, such as lung cancer[13]. Of the eight novel CBL mutations, three displayed relevant E3 ubiquitin activity; S80N/H94Y, Q249E, and W802*. Ectopic expression of these mutations in NSCLC cell lines enhanced cell proliferation and motility[13]. Ectopic expression of wild-type (WT) CBL inhibited NSCLC cell proliferation in vitro and tumor formation in vivo[14]. In the current study, we sought to determine if MET is a target for CBL-mediated degradation and ubiquitination in NSCLC, and whether it could serve as a novel therapeutic target in lung cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
