NTRK Fusion-Positive Cancers and Targeted Therapy

NTRK gene fusions result from chromosomal rearrangements that link the kinase domain of NTRK1, NTRK2 or NTRK3 to various partner genes, generating constitutively active tropomyosin receptor kinases (TRKs) that drive oncogenesis across a spectrum of adult and paediatric malignancies. Although found at low frequency in common tumours such as lung, colorectal and thyroid cancers, and at higher prevalence in rare entities like secretory breast carcinoma and infantile fibrosarcoma, these fusions represent highly actionable targets. The advent of first-generation TRK inhibitors, notably larotrectinib and entrectinib, has established a tumour-agnostic paradigm, delivering brisk and durable systemic and intracranial responses with a manageable safety profile. However, on-target resistance arising from kinase domain mutations has prompted the development of next-generation inhibitors capable of overcoming solvent-front and gatekeeper substitutions. Robust detection strategies—including pan-TRK immunohistochemistry, fluorescence in situ hybridisation and RNA-based next-generation sequencing—are integral to patient selection. Together, these advances underscore a shift towards precision oncology in which molecular diagnosis dictates treatment, offering renewed hope for patients with both common and rare NTRK fusion-positive cancers.

Research from Nature Portfolio

Recent studies have refined computational pipelines for transcriptome-wide fusion detection across thousands of RNA-sequencing profiles, uncovering novel and recurrent kinase gene fusions, including those involving NTRK1, NTRK2 and NTRK3. By surveying diverse tumour types, this work has mapped the pan-cancer distribution of NTRK fusions, expanded the catalogue of actionable fusion partners and highlighted fusion‐driven oncogenic pathways. These findings reinforce the tumour-agnostic framework for TRK inhibitor development and prioritise new fusion variants for preclinical validation and clinical testing.

NTRK Fusion-Positive Cancers and Targeted Therapy publication trend

The graph below shows the total number of articles in ntrk fusion-positive cancers and targeted therapy across all publications each year (not limited to Nature Index journals).

Technical terms

NTRK fusion: Rearrangement of an NTRK gene that creates a chimaeric oncogene driving uncontrolled cell proliferation.

TRK inhibitor: Small-molecule compound that selectively blocks the kinase activity of TRKA, TRKB or TRKC proteins.

RNA-based next-generation sequencing: High-throughput assay detecting gene fusions by sequencing expressed RNA transcripts.

Tumour-agnostic: Treatment approach targeting a molecular abnormality regardless of the tumour’s tissue of origin.

References

1. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Annals of Oncology (2019).
2. TRK inhibitors in TRK fusion-positive cancers. Annals of Oncology (2019).
3. Identifying patients with NTRK fusion cancer. Annals of Oncology (2019).
4. The landscape of kinase fusions in cancer. Nature Communications (2014).
5. NTRK gene fusion testing and management in lung cancer. Cancer Treatment Reviews (2024).
6. Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid TumorsEntrectinib in NTRK+ Solid Tumors: Updated Efficacy/Safety. Clinical Cancer Research (2022).