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

被引：13

作者：

Tan, Yi-Hung Carol ^{[1
]}

Mirzapoiazova, Tamara ^{[2
]}

Won, Brian M. ^{[1
]}

Zhu, Li ^{[3
]}

Srivastava, Minu K. ^{[3
]}

Vokes, Everett E. ^{[1
]}

Husain, Aliya N. ^{[4
]}

Batra, Surinder K. ^{[5
,6
]}

Sharma, Sherven ^{[3
]}

Salgia, Ravi ^{[2
]}

机构：

[1] Univ Chicago Med & Biol Sci, Dept Med, Hematol Oncol Sect, Chicago, IL USA

[2] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA 91010 USA

[3] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA

[4] Univ Chicago Med & Biol Sci, Dept Pathol, Chicago, IL 5 USA

[5] Univ Nebraska, Coll Med, Dept Biochem & Mol Biol, Omaha, NE 68198 USA

[6] Univ Nebraska Med Ctr, Fred & Pamela Buffett Canc Ctr, Omaha, NE USA

来源：

SCIENTIFIC REPORTS | 2017年 / 7卷

关键词：

C-CBL; EPHA2; RECEPTOR; EGFR MUTANTS; MUTATIONS; GROWTH; DEGRADATION; RESISTANCE; FAMILY;

D O I：

10.1038/s41598-017-09078-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

共 36 条

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