Department of Medicine, Section of Hematology/Oncology, The University of Chicago Medicine and Biologic Sciences, Chicago, IL, USA.
Department of Medical Oncology and Therapeutic Research, City of Hope, Duarte, CA, USA.
Sci Rep. 2017 Aug 23;7(1):9192. doi: 10.1038/s41598-017-09078-4.
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.
卡斯蒂亚 B 细胞淋巴瘤（CBL）是一种 E3 泛素连接酶和衔接分子，我们已经证明它在非小细胞肺癌（NSCLC）中很重要。我们研究了 MET 是否是 CBL 的靶点，以及在 CBL 改变的 NSCLC 中是否增强。我们表明，CBL 野生型细胞的 MET 表达低于 CBL 突变型细胞。与野生型细胞相比，CBL 突变型细胞中 MET 的泛素化也减少了。与野生型细胞相比，突变型细胞对 MET 抑制剂 SU11274 也更敏感。sh-RNA 介导的 CBL 敲低增强了 NSCLC 细胞的迁移和集落形成能力，而这些活性被 SU11274 抑制。磷酸激酶组评估显示，涉及 MET、paxillin、EPHA2 和 VEGFR 的途径的磷酸化减少。当在突变细胞系 H1975（厄洛替尼耐药）中敲低 CBL 时，它对 MET 抑制变得敏感。我们的研究结果表明，CBL 状态是 NSCLC 中 MET 靶向治疗的潜在阳性指标。
