Efficacy of larotrectinib in pediatric cancers with NTRK gene fusions - Editorial Commentary

Sep 29, 2026

Editorial commentary discussing the therapeutic rationale for larotrectinib in pediatric malignancies driven by NTRK gene fusions. The article explains how NTRK1-3 encode TRKA/B/C receptors and how fusion events create constitutively active kinase signaling. It reviews the frequency of NTRK fusions across cancer types and highlights fusion biology, including kinase-containing partners, oligomerization domains, and liquid-liquid phase separation and subcellular localization. It also frames clinical context by commenting on elective discontinuation in TRK fusion sarcomas.

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Editorial Commentary

Larotrectinib targets products of NTRK gene fusions

Frequency of NTRK gene fusions in cancer

Figure 1 - TRK downstream signaling pathways

Figure 2 - Characteristics and cellular localization of fusion proteins

Editorial Commentary Efficacy of larotrectinib in pediatric cancers with NTRK gene fusions Peter J. Houghton1^, Mary-Ann Bjornsti2^ 1Department of Molecular Medicine, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 2Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Peter J. Houghton, Ph.D. Department of Molecular Medicine, Greehey Children’s Cancer Research Institute, University of Texas Health Science Center at San Antonio, 8403 Floyd Curl Dr, San Antonio, TX 78229, [USA. Email: houghtonp@uthscsa.edu](USA. Email: houghtonp@uthscsa.edu). Comment on: Mascarenhas L, DuBois SG, Albert CM, et al. Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors. J Clin Oncol 2025;43:1180-7 . Keywords: NTRK gene fusions; infantile fibrosarcoma (IFS); soft tissue sarcoma (STS); elective discontinuation; resistance Submitted Sep 21, 2025. Accepted for publication Dec 01, 2025. Published online Dec 26, 2025. doi: 10.21037/tp-2025-664 View this article at: [https://dx.doi.org/10.21037/tp-2025-664](https://dx.doi.org/10.21037/tp-2025-664) Larotrectinib targets products of NTRK gene fusions Larotrectinib is a potent, selective ATP-competitive inhibitor of tropomyosin-related kinases (TRKs), encoded by NTRK1 , -2 , -3 genes and constitutively activated in multiple cancer types usually by chromosomal translocations. In normal growth and development, theneurotrophic genes NTRK1, NTRK2, and NTRK3 encode neurotrophin receptors TRKA, -B, and-C, respectively. In organogenesis, TRKs are involved in neuronal growth, functional development of neuronal synaptic processes and in processes such as memory development, learning (1) and protection of neurons following trauma (2) . The kinase activity of neurotrophin receptors is activated by ligand binding to the extracellular domain, and subsequent receptor dimerization leads to kinase activation and downstream signaling. Although TRK receptors bind different ligands, activation of each receptor leads to activation of the mitogen activated protein kinase (MAPK), phosphatidylinositol- 3-kinase (PI3K) and phospholipase C-gamma (PLCγ) pathways (Figure 1 ; further detail can be found in references (3,4)] . Oncogenic drivers comprising NTRK genes involve the fusion of the 5' end of over 80 different genes (5), many encoding oligomerization domains (6), with the 3' end of an NTRK gene that encodes the kinase domain. While oligomerization could account for kinase activation (analogous to ligand induced activation of the wild type receptors), recent studies suggest that fusions of genes encoding proteins both with and without oligomerization domains undergo liquid-liquid phase separation (LLPS) becoming concentrated in membrane-less protein granules (7,8), into which downstream signaling components are recruited. Thus, proteins encoded by NTRK gene fusions bear some similarity to the EWS::FLI fusion protein in Ewing sarcoma that also undergoes LLPS (9,10) . A second class of NTRK gene fusions that include the transmembrane domain of the kinase gene may insert into the membranes of the endoplasmic reticulum (Figure 2) (5) . Frequency of NTRK gene fusions in cancer The original NTRK fusion identified involved fusion between the tropmyosin-3 gene ( TPM3) and NTRK1 (11) leading to NTRK fusions being referred to as TRKs. NTRK gene fusions are relatively rare in cancers with adult pancancer frequency estimates of 0.03–0.7%(12) . However, there are cancers where NTRK gene fusions are frequent oncogenic drivers such as secretary carcinomas of breast where NTRK gene fusions are identified in ~90% of ^ ORCID: Peter J. Houghton, 0000-0002-2400-8184; Mary-Ann Bjornsti, 0000-0002-6983-6282. © AME Publishing Company. Transl Pediatr 2025;14(12):3213-3218 | [https://dx.doi.org/10.21037/tp-2025-6

FAQs

What is the mechanism of action of larotrectinib in NTRK fusion cancers?

Larotrectinib is a potent, selective ATP-competitive inhibitor of TRKs, which are activated in cancers by constitutively active NTRK fusion kinases.

How do NTRK gene fusions activate downstream signaling?

NTRK fusions join a 5' partner to the NTRK kinase domain, enabling constant kinase activity and triggering signaling pathways including MAPK, PI3K, and PLCγ.

How common are NTRK gene fusions in cancer, and which pediatric tumors can show them frequently?

Overall adult pancancer estimates are low (about 0.03–0.7%), but certain tumors have much higher rates; the commentary notes high frequencies in secretory carcinomas and infantile fibrosarcoma (IFS).

Sep 29, 2026

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