Development programs for next-generation Trk inhibitors are ongoing. Larotrectinib and entrectinib were approved as tissue-agnostic agents, meaning that the drug can be indicated to patients with Trk fusion genes, independent of the tumor type. To date, the two Trk inhibitors, larotrectinib and entrectinib, were approved by the FDA in 20, respectively ( Cocco et al., 2018). Several TrkA inhibitors have been successfully developed as anticancer drugs. Inhibition of TrkA kinase activity is a promising strategy for cancer therapy based on the deregulated activity of TrkA observed in several cancer types. Trk fusion partners are presumed to affect dimerization, resulting in Trk kinase activation. Since the discovery of TPM3- NTRK1 fusion in colorectal cancer, TrkA activation resulting from gene fusion with various protein partners has been reported in multiple tumor types ( Cocco et al., 2018). The resulting TPM3-TrkA fusion proteins are constitutively active, leading to oncogenesis. Several TrkA fusion protein partners have been identified, including tropomyosin 3 (TPM3), which results in the formation of the TPM3- NTRK1 fusion ( Martin-Zanca et al., 1986 Bongarzone et al., 1989). Fusion of TrkA with various protein partners induces dimerization independent of ligand binding. Chromosomal rearrangements involving the NTRK1 gene result in the formation of TrkA fusion proteins with constitutively activated kinase activity. NTRK1 gene fusions are known to cause deregulation of TrkA signaling. NGF-TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells. TrkA then phosphorylates and activates downstream signaling molecules such as phospholipase Cγ (PLCγ), phosphoinositol-3 kinase, and mitogen-activated protein kinase. Binding of NGF leads to dimerization and phosphorylation of TrkA, resulting in its activation. The TrkA signaling pathway is similar to that of other receptor tyrosine kinases. TrkA was the first member of the Trk receptor family to be characterized, and binds to the nerve growth factor (NGF) ligand. The neurotrophic receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 encode the Trk proteins TrkA, TrkB, and TrkC, respectively ( Khotskaya et al., 2017). The tropomyosin receptor kinase (Trk) family consists of three members, TrkA, TrkB, and TrkC, which serve as receptors for neurotrophins ( Reichardt, 2006). Keywords: Tropomyosin receptor kinase A, Neurotrophic receptor kinase 1 fusion, KRC-108, Colon cancer These results indicate that KRC-108 may be a promising therapeutic agent for Trk fusion-positive cancers. Furthermore, KRC-108 exhibited anti-tumor activity in vivo in a KM12C cell xenograft model. KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt, phospholipase Cγ, and ERK1/2. KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy. KRC-108 inhibited TrkA activity in an in vitro kinase assay, and suppressed the growth of KM12C colon cancer cells harboring an NTRK1 gene fusion. In this study, we evaluated the TrkA-inhibitory activity of the benzoxazole compound KRC-108. Targeting TrkA activity represents a promising strategy for the treatment of cancers that harbor the TrkA fusion protein. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion protein, which is known to cause deregulation of TrkA signaling.
TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its ligand, the nerve growth factor. Abstract Tropomyosin receptor kinase A (TrkA) protein is a receptor tyrosine kinase encoded by the NTRK1 gene.
0 kommentar(er)
