Neurotrophic Receptor Tyrosine Kinase (NTRK) refers to a family of genes that play a role in normal cell function. These genes provide instructions for making proteins that help regulate cell signaling, growth, and survival, particularly in the nervous system. However, when an NTRK gene abnormally joins with another gene, it can lead to uncontrolled cell growth and the development of cancer. These genetic alterations, known as NTRK gene fusions, are uncommon but have been identified in a range of solid tumors.
The NTRK Gene and Its Role in Cancer
The NTRK gene family consists of three members: NTRK1, NTRK2, and NTRK3. These genes produce TRKA, TRKB, and TRKC proteins, respectively. In healthy cells, these TRK proteins are located on the cell surface and act as receptor kinases, mediating signals important for cell development and function, especially within the nervous system, where they promote the growth and survival of nerve cells.
An NTRK gene fusion occurs when a segment of an NTRK gene combines with another gene. This abnormal fusion creates a new, altered TRK protein, known as a TRK fusion protein. Unlike normal TRK proteins, these fusion proteins are continuously active, sending constant growth signals. This uncontrolled signaling drives the proliferation and survival of cancer cells.
NTRK gene fusions are rare but have been identified in over 25 different types of cancer. These fusions have been found in cancers such as non-small cell lung cancer, various sarcomas, and thyroid cancers. Their presence ranges from less than 5% in common cancers like lung or colorectal cancer to over 75% in rare tumor types such as infantile fibrosarcoma and secretory breast carcinoma.
Identifying NTRK Gene Fusions
Detecting NTRK gene fusions requires specialized diagnostic methods. These tests identify the specific genetic changes within a tumor that indicate an NTRK fusion. Several techniques are commonly employed for this purpose.
Next-generation sequencing (NGS) is a comprehensive method for identifying NTRK fusions. It can detect fusions involving any of the three NTRK genes and various partner genes, even those not previously identified. RNA-based NGS is preferred over DNA-based NGS because it more effectively distinguishes between functional gene fusions and other genetic alterations.
Other methods include immunohistochemistry (IHC), which detects TRK proteins in tissue samples. While IHC can be used as an initial screening tool, it lacks the specificity to confirm an NTRK fusion on its own, and positive results usually require confirmation with NGS. Fluorescence in situ hybridization (FISH) is another DNA-based technique that can visualize gene rearrangements on chromosomes, but it often requires knowledge of the specific fusion partners. Reverse transcription polymerase chain reaction (RT-PCR), an RNA-based method, can also identify NTRK fusion transcripts, though it typically requires prior knowledge of both fusion partners.
Targeted Treatments for NTRK Fusion Cancers
The discovery of NTRK gene fusions has led to the development of targeted therapies that inhibit the activity of TRK fusion proteins. Two such drugs, larotrectinib and entrectinib, have received approval for treating NTRK fusion-positive cancers.
Larotrectinib and entrectinib are classified as tyrosine kinase inhibitors. They work by blocking the signaling pathways driven by the constitutively active TRKA, TRKB, and/or TRKC fusion proteins, thereby stopping the uncontrolled growth of cancer cells. These treatments are administered orally.
These targeted therapies have demonstrated effectiveness across a broad range of solid tumors with NTRK gene fusions. Their efficacy is consistent regardless of the specific type of cancer, the tumor’s location in the body, the particular NTRK fusion type, or the patient’s age. Larotrectinib was approved in December 2018 for NTRK-positive solid tumors, and entrectinib received approval in August 2019 for NTRK-positive solid tumors and also for a specific type of lung cancer with a different genetic alteration. Clinical trials for larotrectinib showed an overall response rate of around 75%, and entrectinib demonstrated a response rate of 57% in patients with TRK fusion-positive solid tumors across various cancer types.
What’s Next for NTRK Research
Ongoing research continues to deepen the understanding of NTRK gene fusions and their implications in cancer. Scientists are exploring NTRK fusions as prognostic biomarkers to predict disease progression or patient outcomes. Some studies link NTRK fusions to a favorable course in certain cancers, while others indicate an association with a less favorable prognosis or the development of resistance to current therapies.
Acquired resistance to TRK inhibitors can develop over time, due to new mutations in the NTRK gene or the activation of alternative signaling pathways within cancer cells. Researchers are actively working to understand these resistance mechanisms and develop new strategies, including next-generation TRK inhibitors. Efforts also aim to refine diagnostic methods for NTRK fusions, identify new fusion partners, and develop additional targeted therapies to improve patient outcomes.