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

Nat Commun. 2024 Jun 14;15(1):5110. doi: 10.1038/s41467-024-49499-0.

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.

MeSH terms

  • Anaplastic Lymphoma Kinase / genetics
  • Anaplastic Lymphoma Kinase / metabolism
  • Cell Line, Tumor
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Oncogene Proteins, Fusion* / genetics
  • Oncogene Proteins, Fusion* / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases* / genetics
  • Protein-Tyrosine Kinases* / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-ret* / genetics
  • Proto-Oncogene Proteins c-ret* / metabolism
  • Receptor, trkA / genetics
  • Receptor, trkA / metabolism
  • Signal Transduction / genetics
  • Translocation, Genetic*

Substances

  • Oncogene Proteins, Fusion
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-ret
  • Anaplastic Lymphoma Kinase
  • ROS1 protein, human
  • Receptor, trkA
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RET protein, human
  • ALK protein, human
  • NTRK1 protein, human