Tropomyosin receptor kinase A, Tropomyosin receptor kinase B, Tropomyosin receptor kinase C, ROS proto-oncogene 1, and Anaplastic lymphoma kinase (TRKA/B/C, ROS1, ALK)

The target group comprising Tropomyosin receptor kinase A, B, and C (TRKA/B/C), ROS proto-oncogene 1 (ROS1), and Anaplastic lymphoma kinase (ALK) represents a cluster of receptor tyrosine kinases (RTKs) that are critical drivers in various malignancies when oncogenically activated [1, 3, 15]. These proteins normally function in signal transduction pathways regulating cell growth, differentiation, and survival, with the TRK family playing a specialized role in nervous system development [2, 9, 11]. In many cancers, chromosomal rearrangements lead to the formation of fusion proteins where the kinase domain of these receptors is constitutively active, driving uncontrolled cell proliferation through pathways such as MAPK, PI3K, and PLC-gamma [1, 4, 15]. Drugs like entrectinib and repotrectinib are designed as multi-target inhibitors to address tumors harboring these specific genetic alterations, regardless of the tissue of origin (tumor-agnostic therapy) [1, 10, 15]. Clinical management involves identifying these fusions via next-generation sequencing or immunohistochemistry to select patients for targeted therapy [9, 15, 16]. While effective, these inhibitors are associated with specific safety profiles, including central nervous system effects and metabolic changes like weight gain, reflecting the physiological roles of these kinases in the brain and peripheral tissues [1, 8, 12, 17].

Other names

NTRK1NTRK2NTRK3TrkATrkBTrkCROS1ALKCD246c-rosNeurotrophic receptor tyrosine kinase 1Neurotrophic receptor tyrosine kinase 2Neurotrophic receptor tyrosine kinase 3NTRK1/2/3, ROS1, ALK

ATP-competitive inhibition of the kinase domain of TRKA, TRKB, TRKC, ROS1, and ALK, leading to the suppression of downstream oncogenic signaling pathways such as MAPK/ERK, PI3K/AKT, and PLC-gamma.