Summary

NTRK gene fusions leading to transcription of chimeric TRK proteins drive a wide range of paediatric and adult tumours thereby emerging as targets for TRK inhibition which is now a chief therapeutic goal for patients harbouring TRK expression or activity alterations.

1. Many adult and paediatric tumours are driven by NTRK fusions that encode TRK fusion proteins. Drugs trials are currently underway to address this phenomenon.
2. Rare cancer types (secretory breast carcinoma, mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma) seem to be associated with these alterations much more (>90%), than the other tumour types (usually<1%).
3. In both adult and paediatric patients with NTRK fusion-positive cancers, first-generation TRK tyrosine kinase inhibitors (larotrectinib or entrectinib) have shown histology-agnostic responses which proves that NTRK fusions are clinically actionable.
4. The acquisition of NTRK kinase domain mutations, including solvent-front and gatekeeper mutations lead to resistance to first-generation TRK inhibition, and to overcome these mechanisms of resistance the second-generation TRK inhibitors have been developed.

Neurotrophic tyrosine receptor kinase gene fusions

Vital emergent targets for cancer therapeutics presently include the tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases, since cancer pathogenesis of several hematologic cancers and solid malignancies have been found to be promoted by rearrangements of genes and chromosomes due to the aberrant activities of tyrosine kinases.

Central and peripheral nervous system development and function are preserved by the NTRK (Neurotrophic Tyrosine Receptor Kinase) gene family which encodes three tropomyosin-related kinase (TRK) receptors. The NTRK1, NTRK2, and NTRK3 genes encode the TRK family proteins that consist of these three members, TRKA, TRKB, and TRKC, respectively.

Neurotrophins bind to the extracellular areas and enhance dimerization, phosphorylation, and activation of downstream signalling pathways which end up activating TRK receptors. The RAS/MAPK/ERK, PLC&gamma, and PI3K/Akt are the well-known major downstream pathways. Tumour DNA and RNA sequencing and plasma cell-free DNA profiling are some of the methods for detecting these fusions in the clinic.

The main, soundly authenticated oncogenic event to date is NTRK gene fusions but other events such as other TRK pathway aberrations, protein overexpression, and single nucleotide alterations, TRK protein amplification as well as alternative splicing are also associated with cancer pathogenesis.

Similar to other genes, NTRK genes are also subject to alterations, including fusions and these become oncogenic drivers of various adult and paediatric tumour types. In specific malignancies such as glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas, although rarely but TRK fusion with proteins have been found to promote oncogenesis by mediating constitutive cell proliferation and survival.

TRK inhibitors for treating gene rearrangement-driven tumours

An efficient method of treating gene rearrangement-driven tumours is by targeting gene fusions and chromosomal rearrangements. Therefore, finding targetable, actionable, and druggable chromosomal rearrangements is an ongoing area of research. TRK inhibition is now a chief therapeutic goal for patients harbouring TRK expression or activity alterations. Many trials are currently being undertaken to test TRK-inhibiting compounds in different cancers.

Results of the safety and efficacy trials of TRK fusion kinase receptor inhibitors in patients with NTRK-rearranged malignancies have shown encouraging antitumor activity. In particular, first-generation TRK inhibitors such as larotrectinib and entrectinib have demonstrated potent, safe, and promising TRK inhibition, and treating NTRK fusion-positive cancers patients with larotrectinib and entrectinib results in a high response rate (>75%), regardless of tumour histology.

First-generation TRK inhibitors are generally well tolerated by most patients with the predictable occasional off-tumour, on-target adverse events considering the biological roles of TRK receptors in normal development and adulthood (due to TRK inhibition in non-malignant tissues).

Despite initial robust disease control from the first-generation TRK inhibitors, eventual resistance may be mediated by the acquisition of NTRK kinase domain mutations in many patients which results in advanced-stage NTRK fusion-positive cancers gradually being refractory to TRK inhibition. The second-generation TRK inhibitors which include LOXO-195 and TPX-0005 are currently under trial to ascertain if they can overcome some of these certain resistance mutations.