NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

Authors: Alessandro Gambella et al. (2020)

Link: https://doi.org/10.3390/ijms21030753
 

Background Information:

NTRK genes (NTRK1, NTRK2, NTRK3) encode TRK receptors—proteins on nerve cells that respond to signals guiding brain development and nerve cell survival. Sometimes, due to a rare genetic event, NTRK genes fuse with another gene. These fusions create permanently active receptors that drive uncontrolled cell growth, which can lead to cancer. While these NTRK gene fusions are uncommon overall, they are emerging as important disease-causing factors in certain brain tumors, raising hope for new targeted treatments.

Purpose of the Study:

The purpose of this review was to explore NTRK fusions specifically in central nervous system (CNS) tumors—like gliomas and pediatric brain cancers—where effective treatments are lacking. The authors sought to explain how often these fusions occur, how they can be accurately diagnosed, and whether therapies targeting them—such as TRK-inhibitor drugs—might offer new hope to patients.

Methods and Data Analysis:

As a review, no new lab experiments were performed. Instead, the authors gathered and analyzed published studies detailing: the biological role of TRK receptors; how NTRK fusions drive cancer in the brain; the frequency of these fusions in various CNS tumors (using a summarized table); diagnostic methods (like lab tests and genetic sequencing); and early findings on drugs that block TRK activity.

Key Findings and Conclusions:

NTRK fusions are rare in most CNS tumors—typically under 1% in adult glioblastoma—but occur more frequently (up to 10–40%) in select pediatric brain tumors like infant high-grade gliomas. Detecting these fusions requires careful testing using multiple methods (such as immunohistochemistry, FISH, and DNA/RNA sequencing), each with unique strengths and drawbacks. Crucially, when NTRK fusions are found, TRK-inhibitor drugs (e.g., larotrectinib, entrectinib) have shown striking effectiveness across various tumor types. The authors conclude that identifying NTRK fusions in brain tumors is both diagnostically and therapeutically significant, and that their detection should be integrated into standard tumor testing.

Applications & Limitations:

Clinically, the review supports routine testing for NTRK fusions in brain tumors with few treatment options—particularly in children—so that patients may benefit from targeted TRK-blocking drugs. However, limitations include low overall fusion rates in most tumors, variable sensitivity of diagnostic tests, and the fact that current evidence mostly comes from early phase studies and case series rather than large clinical trials. Future work must refine cost-effective, accurate testing methods and evaluate long-term responses to TRK inhibitors in CNS tumor patients.