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Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Ed S Kheder1, David S Hong2

  • 1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 11, 2018
PubMed

Insights

Chromosomal rearrangements drive cancer, but targeting them is difficult. Neurotrophic Tyrosine Receptor Kinase (TRK) fusions are key oncogenic drivers, and TRK inhibitors like larotrectinib show promise in treating these rare cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Chromosomal rearrangements are recognized drivers of hematologic and solid malignancies.
  • Identifying actionable chromosomal rearrangements for targeted therapy remains a significant challenge in cancer treatment.
  • Neurotrophic Tyrosine Receptor Kinase (TRK) gene fusions are oncogenic alterations found in various cancers.

Purpose of the Study:

  • To discuss the oncogenic role of TRK fusion proteins in diverse malignancies.
  • To highlight the clinical efficacy and safety of TRK inhibitors in treating NTRK-rearranged tumors.
  • To review ongoing clinical trials investigating targeted therapies for TRK fusion-driven cancers.

Main Methods:

  • Review of preclinical studies on TRK fusion protein oncogenesis.
  • Analysis of clinical trial data for TRK fusion kinase receptor inhibitors.
  • Discussion of the mechanism of action for TRK inhibitors like larotrectinib and entrectinib.

Main Results:

  • TRK fusion proteins promote cancer by driving constitutive cell proliferation and survival.
  • TRK inhibitors, including larotrectinib and entrectinib, demonstrate significant antitumor activity.
  • Clinical trials show encouraging safety and efficacy profiles for TRK inhibitors in patients with NTRK-rearranged malignancies.

Conclusions:

  • Targeting TRK fusions represents a viable therapeutic strategy for specific cancer types.
  • Larotrectinib and entrectinib are potent and promising inhibitors for TRK fusion-driven cancers.
  • Further clinical investigation of TRK inhibitors is warranted for various malignancies.

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