Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.
Taek-Chin CheongAhram JangQi WangGiulia C LeonardiBiagio RicciutiJoao V AlessiAlessandro Di FedericoMark M AwadMaria K LehtinenMarian H HarrisRoberto ChiarlePublished in: Nature communications (2024)
Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- transcription factor
- end stage renal disease
- advanced non small cell lung cancer
- genome wide
- endothelial cells
- ejection fraction
- chronic kidney disease
- protein protein
- single cell
- magnetic resonance
- peritoneal dialysis
- prognostic factors
- drug delivery
- computed tomography
- reactive oxygen species
- cancer therapy
- human immunodeficiency virus
- binding protein
- men who have sex with men
- hiv infected
- oxidative stress
- genome wide analysis
- childhood cancer