TRK Inhibitors Advance Rapidly in "Tumor-Agnostic" Paradigm

Although oncogenic fusions involving the neurotrophic tropomyosin receptor kinase (NTRK) genes were first noted more than 30 years ago, the growing use of next-generation sequencing has only recently revealed their presence across a wide range of tumor types and piqued interest in their potential as anticancer targets.

Just as ALK inhibitors developed quickly as a lung cancer treatment, drugs targeted at the tropomyosin receptor kinase (TRK) protein family, encoded by the NTRK genes, are following a rapid bench-to-bedside trajectory. The FDA has granted breakthrough therapy designations to entrectinib and larotrectinib (LOXO-101) for patients with metastatic NTRK fusion–positive solid tumor types, and several other agents are being tested in clinical trials (Table).

Meanwhile, the development of acquired resistance is already being addressed by the advancement into clinical testing of secondgeneration agents with efficacy in resistant tumors, even before the first generation has received FDA approval.

Most intriguingly, the low prevalence of NTRK fusions in individual tumor types has necessitated the use of novel clinical trial designs, such as basket trials. The astonishing efficacy of TRK inhibitors in NTRK fusion–positive patients, regardless of histology, exemplifies the potential of the “tumor-agnostic” treatment paradigm.

The TRK Pathway

In the mid-1980s, an oncogenic fusion of the TPM3- NTRK1 genes, observed in a colon tumor sample, was among the first chromosomal rearrangements identified in cancer.¹ Since then, this type of molecular abnormality has been widely recognized as a driving event in a broad array of tumor types², and the development of drugs designed to target such aberrations has greatly improved outcomes in some forms of cancer.

NTRK1 encodes the TRK A protein that, together with TRK B and C (encoded by the NTRK2 and NTRK3 genes, respectively), form the TRK family of proteins. These receptors conduct signaling pathways that play a key role in the development of the central and peripheral nervous systems.

TRK signaling is activated by the binding of neurotrophin ligands, predominantly nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3); they bind, respectively, to TRK A, B, and C (Figure).^3-5 As with other tyrosine kinase receptor–driven pathways, ligands bind to the part of the receptor that extends out of the cell. This causes 2 receptor molecules to pair up, driving phosphorylation of critical tyrosine residues on the portion of the receptor that protrudes into the cell and creating docking sites for intracellular proteins that contain specific domains.

  In this manner, the signal is transduced inside the cell and subsequently propagated further downstream as the recruited adaptor proteins turn on other pathways, including PI3K, MAPK, and PLCγ. Ultimately, the signal reaches the nucleus, initiating a variety of transcriptional programs that mediate cellular outcomes, in this case regulating the proliferation, growth, and survival of neurons.

Role of Gene Fusions

Since the early reports of the TPM3-NTRK1 fusion, a variety of NTRK gene abnormalities have been described in different tumor types, including amplifications, deletions, mutations, and altered splicing of TRK messenger RNA (mRNA) transcripts. Few of these abnormalities have been functionally characterized, and even fewer have been proven to be oncogenic, with the exception of an in-frame deletion and mRNA splice variant in acute myeloid leukemia and neuroblastoma, respectively.

The best-characterized oncogenic role is for chromosomal rearrangements involving the NTRK genes. Most commonly, these rearrangements result in gene fusions in which the NTRK gene is broken apart, and the portion containing the kinase domain is fused back together next to a different gene, causing the TRK protein to become activated even in the absence of its ligand. This promotes cancer formation by driving several of the cancer hallmarks, including unchecked cell proliferation and growth, through the TRK pathway.

The development of next-generation sequencing technologies has greatly expanded appreciation of the role of NTRK fusions in the development of cancer. To date, multiple fusion partners that play oncogenic roles across 19 tumor types have been identified for all 3 NTRK genes.^3-5