High affinity nerve growth factor receptor (TRKA) fusions (TRKA fusions)

TRKA fusions are oncogenic drivers resulting from the chromosomal rearrangement of the NTRK1 gene with various partner genes, such as TPM3, LMNA, or TPR. These fusions lead to the constitutive, ligand-independent activation of the TRKA kinase domain, which triggers downstream signaling pathways including MAPK/ERK, PI3K/AKT, and PLC-gamma to promote uncontrolled cell proliferation and survival [1, 2]. While wild-type TRKA is a receptor tyrosine kinase essential for the development and maintenance of the central and peripheral nervous systems through its interaction with nerve growth factor (NGF), the fusion variants are found in a diverse array of adult and pediatric solid tumors [1, 5]. Clinically, TRKA fusions are highly significant as they represent actionable targets for tumor-agnostic therapies. Selective tyrosine kinase inhibitors, such as larotrectinib and entrectinib, have shown remarkable efficacy in patients harboring these fusions regardless of the primary tumor site [3, 6]. Despite their success, the development of acquired resistance through kinase domain mutations, such as the G595R solvent front mutation, necessitates the use of next-generation inhibitors like repotrectinib [4, 7]. References: [1] UniProt (P04629); [2] National Cancer Institute (NCI) - NTRK Gene Fusions; [3] FDA - Larotrectinib Approval (2018); [4] Drilon et al., NEJM (2018); [5] Vaishnavi et al., Cancer Discovery (2015); [6] Doebele et al., Lancet Oncology (2020); [7] Cocco et al., Nature Reviews Clinical Oncology (2018).

Other names

NTRK1 fusionsTropomyosin receptor kinase A fusionsTRKA rearrangementsNTRK1 rearrangementsMTC fusions

Selective inhibition of the tropomyosin receptor kinase (TRK) family proteins (TRKA, TRKB, and TRKC) by competing with ATP for the kinase domain, thereby blocking downstream signaling pathways such as MAPK, PI3K, and PLC-gamma [3, 4, 7].