Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance

Alison M Schram1, Matthew T Chang2, Philip Jonsson2

  • 1Department of Medicine 1275 York Avenue, New York, New York 10065, USA.

Insights

Gene fusions in solid tumors drive cancer. Targeted therapies like tyrosine-kinase inhibitors (TKIs) are effective but lead to resistance, prompting development of new TKIs and sequential treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Structural gene rearrangements leading to gene fusions are common in solid tumors.
  • Identifying activating gene fusions aids in tumor diagnosis and targeted treatment.
  • Targeted therapies against oncogenic tyrosine kinases have shown success in specific cancers.

Purpose of the Study:

  • To review the role of gene fusions in solid tumors.
  • To discuss the efficacy and limitations of tyrosine-kinase inhibitors (TKIs).
  • To explore emerging treatment strategies for overcoming TKI resistance.

Main Methods:

  • Literature review of studies on gene fusions and targeted therapies in solid tumors.
  • Analysis of mechanisms of acquired resistance to TKIs.
  • Evaluation of second- and third-generation TKIs and sequential treatment approaches.

Main Results:

  • Activating gene fusions are crucial biomarkers for targeted therapy in various solid tumors.
  • Tyrosine-kinase inhibitors (TKIs) targeting ALK, ROS1, PDGFB, RET, NTRK, FGFR, and BRAF/CRAF fusions demonstrate clinical efficacy.
  • Acquired resistance to TKIs, driven by mutations or bypass pathways, necessitates the development of next-generation inhibitors and strategic treatment sequencing.

Conclusions:

  • Gene fusions represent important therapeutic targets in oncology.
  • Overcoming acquired resistance to TKIs is critical for long-term patient benefit.
  • Sequential administration of different TKIs is a promising strategy for managing TKI-resistant tumors.

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