Related Experiment Video
Updated: Nov 20, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
How selecting best therapy for metastatic NTRK fusion-positive non-small cell lung cancer?
1Thoracic Oncology Center, Karolinska University Hospital/Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Abstract:
The tropomyosin receptor kinase (TRK) family of receptor tyrosine kinases has become a focus of clinical interest because the NTRK genes (NTRK1-3) encoding them have been identified as oncogenic fusion genes in a wide range of different tumor types, including lung cancer. These NTRK gene fusions usually occur at a low frequency below 1%, in non-small cell lung cancer (NSCLC) in 0.1-0.2% of the cases and have been reported across a wide range of tumor types. The TRK fusion proteins encoded by such gene fusions have constitutively activated tyrosine kinase domains and constitute actionable targets for tyrosine kinase inhibitors (TKIs). The first generation TRK TKIs larotrectinib and entrectinib have been investigated in clinical phase I and II trials in solid tumors both in adult and pediatric patients and results have demonstrated high response rates that are durable and with generally good tolerability. This has led to approval of these TRK inhibitors by regulatory authorities in the USA, Europe and Japan as tumor agnostic treatment of advanced or recurrent NTRK fusion-positive cancers in adult and pediatric patients. With a focus on lung cancer, this review gives a background to NTRK fusion genes, presents clinical data for TRK inhibitors and discuss the issue of acquired resistance to TRK inhibition.
Insights
NTRK gene fusions in cancers, including lung cancer, create actionable targets for TRK inhibitors. Larotrectinib and entrectinib show durable responses, leading to tumor-agnostic approvals for NTRK fusion-positive cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tropomyosin receptor kinase (TRK) family kinases are crucial in cell signaling.
- NTRK gene fusions (NTRK1-3) are oncogenic drivers across various cancers, including non-small cell lung cancer (NSCLC).
- TRK fusions result in constitutively active kinase domains, presenting therapeutic targets.
Purpose of the Study:
- To review the role of NTRK gene fusions in cancer development.
- To present clinical data on TRK inhibitors for NTRK fusion-positive solid tumors.
- To discuss acquired resistance mechanisms to TRK inhibition.
Main Methods:
- Review of clinical trial data for TRK inhibitors (larotrectinib, entrectinib).
- Analysis of efficacy and tolerability in adult and pediatric patients.
- Discussion of resistance mechanisms in the context of TRK inhibition.
Main Results:
- TRK inhibitors demonstrate high and durable response rates in patients with NTRK fusion-positive solid tumors.
- Larotrectinib and entrectinib are approved for tumor-agnostic treatment of advanced or recurrent NTRK fusion-positive cancers.
- Generally good tolerability profiles were observed for these TRK inhibitors.
Conclusions:
- NTRK gene fusions are important oncogenic drivers actionable by TRK inhibitors.
- TRK inhibitors represent a significant advancement in treating NTRK fusion-positive cancers.
- Understanding and overcoming acquired resistance is crucial for long-term efficacy.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:56Treatment Resistant Cancers
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:27Tumor Immunotherapy