The Neurotrophic Receptor Tyrosine Kinase (NTRK) gene encodes a family of cell surface proteins called Tropomyosin Receptor Kinases (TRKs). The discovery of specific alterations in the NTRK gene has led to a shift toward targeted cancer treatments in modern oncology. Understanding the normal biological role of these receptors and how they are hijacked by cancer cells is fundamental to appreciating this precision medicine approach.
The Normal Function of NTRK Receptors
The NTRK genes (NTRK1, NTRK2, and NTRK3) encode the receptor proteins TRKA, TRKB, and TRKC. These receptors are primarily expressed on the surface of nerve cells, regulating fundamental processes in the nervous system by acting as receivers for signaling molecules called neurotrophins. Neurotrophins, such as Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), bind to the TRK receptors. This binding causes the receptors to pair up and become activated (dimerization and phosphorylation), initiating complex signaling cascades inside the cell. These pathways promote the survival, differentiation, and growth of neurons, particularly during development.
How NTRK Gene Fusions Drive Cancer Growth
A gene fusion transforms the normal NTRK receptor into a cancer-driving engine. This occurs when a piece of the NTRK gene connects with an unrelated partner gene, creating a hybrid gene and a resulting chimeric protein. The partner protein segment forces the TRK portion of the fusion protein to dimerize constantly. This permanent pairing leads to the constitutive activation of the TRK kinase domain, meaning the receptor is “always on” without its natural ligand. This uncontrolled, continuous signaling mimics the normal growth signal, leading to runaway cell proliferation and survival, which are the hallmarks of cancer.
Screening and Identifying NTRK-Positive Tumors
Identifying an NTRK gene fusion is necessary before targeted treatment begins. While these fusions are rare (less than 1%) in common adult cancers like lung or colorectal cancer, they are highly prevalent in certain rare tumors. For example, NTRK fusions are found in over 90% of congenital infantile fibrosarcoma and secretory breast carcinoma cases.
Specialized testing methods are required to detect these genetic rearrangements accurately. Next-Generation Sequencing (NGS) is the most comprehensive method, detecting the fusion and identifying the exact partner gene. RNA-based NGS is often favored over DNA-based methods because it focuses on the functional messenger RNA transcript, avoiding the difficulty of sequencing large, complex non-coding regions.
Screening Tools
Other techniques are utilized as screening tools. Fluorescence In Situ Hybridization (FISH) uses fluorescent probes to detect the physical break-apart of the NTRK gene on the chromosome. Pan-TRK Immunohistochemistry (IHC) is a cost-effective method that detects the over-expression of the TRK protein, which indicates a fusion, though a positive IHC result requires confirmation with a molecular test like NGS.
The Role of TRK Inhibitors in Treatment
The discovery of the NTRK fusion mechanism led to the development of TRK inhibitors, such as larotrectinib and entrectinib. These small-molecule drugs are designed to fit into the active site of the abnormal fusion protein, blocking its continuous signaling activity. By disabling the constitutively active kinase domain, these inhibitors shut down the growth and survival pathways upon which cancer cells depend.
This treatment is “tissue-agnostic,” meaning the drug is approved for use against any solid tumor harboring an NTRK gene fusion, regardless of the cancer’s origin. Clinical trials have demonstrated high objective response rates, often exceeding 75% across various adult and pediatric tumor types. Furthermore, entrectinib and larotrectinib can cross the blood-brain barrier, providing effective treatment for patients whose cancer has spread to the central nervous system.
Addressing Resistance
Although TRK inhibitors are initially effective, cancer cells can eventually develop resistance through new genetic mutations. The most common acquired resistance involves mutations within the TRK kinase domain that prevent the drug from binding effectively. To address this challenge, second-generation TRK inhibitors have been developed to target these specific resistance mutations, offering subsequent treatment options.