The process of tumorigenesis frequently involves protein kinase activation events, which can result from either mutations, or chromosomal rearrangements. Gene rearrangements, leading to the expression of constitutively activated fusion tyrosine kinase receptors, have been increasingly identified as a common feature of malignancies over the last three decades, and success has been demonstrated using these rearrangements as targets for drug development. The expression of such gene fusions in a tumor can create a phenomenon termed 'oncogene addiction' in which the tumor becomes dependent on signaling by the aberrant kinase pathway, thus rendering its survival and continued proliferation exquisitely sensitive to targeted inhibition with small molecule tyrosine kinase inhibitor drugs. Expression of the proteins encoded by these tyrosine kinase fusion genes can, in most cases, be shown to function independently as oncogenic drivers, capable of activating critical downstream pathways involved in the malignant phenotype, resulting in transformation of cells in vitro. Some of the most important kinases that have been shown to undergo rearrangement in human cancers include the anaplastic lymphoma kinase (ALK), ROS1 kinase, and the neurotrophic receptor tyrosine kinases (NTRKs).<unk>  is a selective tyrosine kinase inhibitor with specificity, at low nanomolar concentrations, for all of three Trk proteins (encoded by the NTRK1, 2, and 3 genes, respectively) as well as the ROS1, and ALK receptor tyrosine kinases. The drug is orally administered, once daily, and is being studied in patients whose tumors have been shown to have fusions in NTRK1/2/3, ALK, or ROS1. As a ROS1 inhibitor,<unk>  has demonstrated in cellular anti-proliferative studies to have a 36-fold greater potency against ROS1 as compared with another commercially available ROS1 inhibitor, crizotinib. Target TrkA TrkB TrkC ROS1 ALK IC50 (nM) 1.7 0.1 0.1 0.2 1.6<unk>  has also demonstrated in-vitro efficacy against potential Trk inhibitor resistance mutations such as NTRK1 F589L, NTRK1 V573M, NTRK1 G667S.
Entrectinib
Dabrafenib
Neratinib
Selpercatinib
Tucatinib
Baricitinib
Fostamatinib
Encorafenib