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

Taek-Chin Cheong (), Ahram Jang, Qi Wang, Giulia C. Leonardi, Biagio Ricciuti, Joao V. Alessi, Alessandro Di Federico, Mark M. Awad, Maria K. Lehtinen, Marian H. Harris and Roberto Chiarle ()
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Taek-Chin Cheong: Boston Children’s Hospital and Harvard Medical School
Ahram Jang: Boston Children’s Hospital and Harvard Medical School
Qi Wang: Boston Children’s Hospital and Harvard Medical School
Giulia C. Leonardi: Boston Children’s Hospital and Harvard Medical School
Biagio Ricciuti: Dana-Farber Cancer Institute
Joao V. Alessi: Dana-Farber Cancer Institute
Alessandro Di Federico: Dana-Farber Cancer Institute
Mark M. Awad: Dana-Farber Cancer Institute
Maria K. Lehtinen: Boston Children’s Hospital and Harvard Medical School
Marian H. Harris: Boston Children’s Hospital and Harvard Medical School
Roberto Chiarle: Boston Children’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-49499-0

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