Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.

Autor: Cheong TC; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA. taekchin.cheong@childrens.harvard.edu., Jang A; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA., Wang Q; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Leonardi GC; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.; Department of Biomedical and Biotechnological Sciences, University of Catania, 95123, Catania, Italy., Ricciuti B; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Alessi JV; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Di Federico A; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Awad MM; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA., Lehtinen MK; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Harris MH; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Chiarle R; Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA. roberto.chiarle@childrens.harvard.edu.; Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, 10126, Italy. roberto.chiarle@childrens.harvard.edu.; Division of Hematopathology, IEO European Institute of Oncology IRCCS, 20141, Milan, Italy. roberto.chiarle@childrens.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 14; Vol. 15 (1), pp. 5110. Date of Electronic Publication: 2024 Jun 14.
DOI: 10.1038/s41467-024-49499-0
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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