Exploring the path to selective TRK inhibition

TRK Fusions

TRKs consist of a family of 3 cell receptor proteins known as TRKA, TRKB, and TRKC and are encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively

Neurotrophic tyrosine receptor kinase (NTRK) 1-3 are protein coding genes contained within the DNA of a cell that provide instructions for synthesizing proteins, the blueprint for cellular communication. The NTRK1-3 genes encode for the tropomyosin receptor kinase (TRK) family of receptor proteins that sit on the surface of cells, providing instructions to the cell for how to behave. NTRKs are important for neuronal regulation.

Under normal conditions, TRK receptors are found primarily in neurons and become activated when they bind to proteins circulating outside the cell (such proteins are referred to as “ligands”). For TRK, the activating ligands are collectively referred to as neurotrophins (NTs) and individually known as nerve growth factor, brain-derived neurotrophic factor, NT-3, and NT-4. NTs bind to TRK receptors, causing activation of their associated kinases. In turn, these signaling pathways help regulate how neurons function in the setting of pain, cognition, movement, memory, and mood.

Cell Receptors

Genomic alterations in NTRK may be oncogenic

Research during the last several years has generated interest in TRK as a potential target for cancer therapeutics. Simultaneously, next-generation sequencing methods are increasingly identifying NTRK1-3 as “drivers” of tumor growth based on their roles in gene fusion events. Gene fusions occur when 2 chromosomes break apart and the wrong pieces fuse back together forming a hybrid gene that can activate a signaling pathway. When this happens in a cancer cell, the fused gene is like a light switch that is always in the “on” position, causing tumor growth.

Gene Fusion and Mutation Gene Amplification and Protein Overexpression

Patients with advanced cancer who seek out tumor profiling or comprehensive cancer genetic testing may discover that their tumor harbors a TRK fusion, as this genetic event has been described across many tumor types, including: 

  • Acute myeloid leukemia
  • Astrocytoma
  • Brain low-grade glioma
  • Breast cancer
  • Colorectal cancer
  • Congenital mesoblastic nephroma
  • Gastrointestinal stromal tumors
  • Glioblastoma multiforme
  • Head and neck squamous cell cancer
  • Infantile fibrosarcoma
  • Intrahepatic cholangiocarcinoma
  • Lung cancer
  • Mammary analog secretory carcinoma of salivary gland origin
  • Melanoma
  • Sarcoma
  • Secretory breast cancer
  • Thyroid cancer
Chromosome Gene Fusion Chromosome Gene Fusion

To date, there is little scientific evidence that mutations and amplifications in the NTRK genes or protein overexpression of the TRK proteins can drive cancer. Unlike gene fusions, NTRK mutations, gene amplifications, and TRK protein overexpression are likely “passenger” events that play a less direct role in tumor growth. For this reason, larotrectinib (LOXO-101) clinical development is primarily focused on NTRK gene fusions.

Explore Larotrectinib Clinical Trials

TRK Fusion Fact Sheet