Gene fusions occur when two unrelated genes abnormally join, often due to a break in chromosomes and a subsequent rejoining in an incorrect order. This genetic rearrangement can lead to the creation of a new, hybrid gene. Among these, NTRK gene fusions are a specific type involving the NTRK (Neurotrophic Tyrosine Receptor Kinase) family of genes. These fusions are recognized as drivers of cancer growth in certain tumors. Their identification has opened avenues for targeted therapeutic approaches.
Understanding NTRK Fusion
The NTRK gene family (NTRK1, NTRK2, and NTRK3) provides instructions for making TRK proteins (TRKA, TRKB, and TRKC). Under normal conditions, TRK proteins are receptor tyrosine kinases on cell surfaces, regulating cell growth, differentiation, and survival, particularly in the nervous system. They are activated when specific growth factors, called neurotrophins, bind to them, causing the receptors to pair up and activate internal signaling pathways.
NTRK gene fusions arise when a segment of a chromosome containing an NTRK gene breaks off and fuses with a portion of another, unrelated gene, known as a “fusion partner.” This creates a chimeric gene producing an altered TRK fusion protein. This fusion protein is continuously active, signaling uncontrollably without needing external neurotrophin signals. The constant activation bypasses normal cellular controls, promoting sustained growth and survival signals within the cell.
Role in Cancer Development
The constitutively active TRK fusion protein drives uncontrolled cell growth and survival, leading to cancer. These abnormal proteins continuously send signals through cellular pathways, such as the RAS/MAPK and PI3K/AKT pathways, which are normally involved in cell proliferation and survival. When these pathways are constantly “on,” cells divide without regulation and avoid programmed cell death, accumulating to form a tumor. This makes NTRK fusions “oncogenic drivers.”
NTRK fusions have been identified in a range of adult and pediatric solid tumors. While they can appear in more than 25 different cancer types, their prevalence varies significantly. They are particularly common in certain rare cancers, such as secretory carcinomas of the breast and salivary glands, infantile fibrosarcoma, and congenital mesoblastic nephroma. These fusions are also found, though less frequently, in more common cancers like lung cancer, thyroid cancer, colorectal cancer, and certain sarcomas and gliomas.
Identifying NTRK Fusions
Testing for NTRK fusions is important for cancer patients, especially those with certain tumor types or who might benefit from targeted therapies. Accurate identification allows for specific treatment decisions. Several diagnostic methods are used to detect these genetic alterations.
One common method is RNA-based next-generation sequencing (NGS). This technique analyzes RNA to detect fusion transcripts, which are the products of fused genes, providing a highly precise way to identify both known and novel fusion partners regardless of the breakpoint location. Fluorescence in situ hybridization (FISH) uses fluorescent probes to visualize gene rearrangements on chromosomes. While FISH can detect rearrangements, it does not identify the specific fusion partner or confirm protein production. Immunohistochemistry (IHC) is a screening tool. IHC detects the presence of TRK fusion proteins, but a positive IHC result typically requires confirmation with a molecular test like NGS, as it can also detect normal TRK proteins.
Targeted Therapies for NTRK Fusion Cancers
The discovery of NTRK fusions has led to the development of “precision medicine” or “targeted therapy” approaches. These therapies are designed to specifically block the activity of the abnormal TRK fusion protein, rather than broadly attacking all rapidly dividing cells like traditional chemotherapy. This focused approach offers more effective treatments with fewer side effects.
TRK inhibitors counteract the continuous signaling of the TRK fusion proteins. These inhibitors bind to the TRK protein’s active site, preventing activation of pathways that promote tumor growth. Examples of approved TRK inhibitors include larotrectinib and entrectinib. Larotrectinib is a highly selective inhibitor of all three TRK proteins, while entrectinib is a multi-kinase inhibitor that also targets ROS1 and ALK proteins. These therapies have shown high response rates, often exceeding 75%, across various cancer types when an NTRK fusion is present. Patients experience improved outcomes and a more favorable side effect profile than conventional treatments. However, cancer cells can develop resistance mechanisms, such as new mutations in the NTRK kinase domain or activation of alternative signaling pathways.