Oncogenic Function of a KIF5B-MET Fusion Variant in Non-Small Cell Lung Cancer

Abstract

A kinesin family member 5b (KIF5B)-MET proto-oncogene, receptor tyrosine kinase (MET) rearrangement was reported in patients with lung adenocarcinoma but its oncogenic function was not fully evaluated. We used one-step reverse transcription-polymerase chain reaction for RNA samples to screen for the KIF5B-MET fusion in 206 lung adenocarcinoma and 28 pulmonary sarcomatoid carcinoma patients. Genomic breakpoints of KIF5B-MET were determined by targeted next-generation sequencing. Soft agar colony formation assays, proliferation assays, and a xenograft mouse model were used to investigate its oncogenic activity. In addition, specific MET inhibitors were administered to evaluate their anti-tumor activities. A KIF5B-MET fusion variant in a patient with a mixed-type adenocarcinoma and sarcomatoid tumor was identified, and another case was found in a pulmonary sarcomatoid carcinoma patient. Both cases carried the same chimeric gene, a fusion between exons 1–24 of KIF5B and exons 15–21 of MET. KIF5B-MET-overexpressing cells exhibited significantly increased proliferation and colony-forming ability. Xenograft tumors harboring the fusion gene demonstrated significantly elevated tumor growth. Ectopic expression of the fusion gene stimulated the phosphorylation of KIF5B-MET as well as downstream STAT3, AKT, and ERK1/2 signaling pathways. The MET inhibitors significantly repressed cell proliferation; phosphorylation of downstream STAT3, AKT, and ERK1/2; and xenograft tumorigenicity. In conclusion, the KIF5B-MET variant was demonstrated to have an oncogenic function in cancer cells. These findings have immediate clinical implications for the targeted therapy of subgroups of non-small cell lung cancer patients.

Autophagy Regulatory Genes MET and RIPK2 Play a Prognostic Role in Pancreatic Ductal Adenocarcinoma: A Bioinformatic Analysis Based on GEO and TCGA

“…RAC1 can also be activated by MET-associated complex in various cancer cells and promotes migration and invasion [ 38 ]. KIF5B gene and MET gene were reported to fuse in lung cancer, which causes elevated tumor growth [ 39 , 40 ]. The role of RIPK2 in autophagy in tumors is unclear.…”

Novel intergenic KIF5B-MET fusion variant in a patient with gastric cancer: A case report

“…MET fusions are rare in GC, and this is the first documented case of a patient with an MET fusion-positive tumor. We identified a fusion variant involving KIF5B-MET , and the variant was the same as the most recently reported KIF5B-MET fusion variant in non-small cell lung cancer[ 10 ]. This fusion gene was initially reported in one of 513 lung adenocarcinoma samples[ 11 ].…”

Case report: A Novel Intergenic KIF5B-MET Fusion Variant in a Patient with Gastric Cancer

“…Our identi ed KIF5B-MET variant was the same as the most recently reported KIF5B-MET fusion variant in non-small cell lung cancer (NSCLC). 10 This fusion gene was initially reported in one of 513 lung adenocarcinoma samples. 11 Although several MET inhibitors have been approved for the treatment of MET-positive patients, the tumor response is heterogeneous, and the OS ranges from 1 to 36 months.…”

“…11 Although several MET inhibitors have been approved for the treatment of MET-positive patients, the tumor response is heterogeneous, and the OS ranges from 1 to 36 months. 10,12,13 One explanation is that the response of MET inhibitors to different MET fusion types differs. Other possible reasons include the existence of other driver mutations or primary resistance mutations in the kinase structure of the MET protein.…”