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Boston Children's Hospital and Harvard Medical School

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Nat. Commun., Jun 14 2024, 15 (1) 5110 | https://doi.org/10.1038/s41467-024-49499-0 Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers

Taek-Chin Cheong^1,7,*, Ahram Jang ^1,2,7, Qi Wang¹, Giulia C. Leonardi ^1,3, Biagio Ricciuti ⁴, Joao V. Alessi ⁴, Alessandro Di Federico ⁴, Mark M. Awad ⁴, Maria K. Lehtinen ¹, Marian H. Harris ¹ & Roberto Chiarle^1,5,6,*

¹Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
²Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
³Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy.
⁴Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
⁵Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
⁶Division of Hematopathology, IEO European Institute of Oncology IRCCS, 20141 Milan, Italy.
⁷These authors contributed equally: Taek-Chin Cheong, Ahram Jang.

^*Corresponding authors: correspondence to Taek-Chin Cheong or Roberto Chiarle

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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-21)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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