Tropomyosin receptor
kinase A (TrkA)
protein is a
receptor tyrosine kinase encoded by the NTRK1 gene. TrkA signaling mediates the proliferation, differentiation, and survival of neurons and other cells following stimulation by its
ligand, the
nerve growth factor. Chromosomal rearrangements of the NTRK1 gene result in the generation of TrkA fusion
protein, which is known to cause deregulation of TrkA signaling. Targeting TrkA activity represents a promising strategy for the treatment of
cancers that harbor the TrkA fusion
protein. In this study, we evaluated the TrkA-inhibitory activity of the
benzoxazole compound
KRC-108.
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.
KRC-108 treatment induced cell cycle arrest, apoptotic cell death, and autophagy.
KRC-108 suppressed the phosphorylation of downstream signaling molecules of TrkA, including Akt,
phospholipase Cγ, and ERK1/2. Furthermore,
KRC-108 exhibited anti-
tumor activity in vivo in a KM12C cell xenograft model. These results indicate that
KRC-108 may be a promising therapeutic agent for Trk fusion-positive
cancers.