Merestinib is an oral multi-kinase inhibitor targeting a limited number of 
oncokinases including MET, AXL, RON and MKNK1/2. Here, we report that merestinib 
inhibits neurotrophic receptor tyrosine kinases NTRK1/2/3 which are oncogenic 
drivers in tumors bearing NTRK fusion resulting from chromosomal rearrangements. 
Merestinib is shown to be a type II NTRK1 kinase inhibitor as determined by 
x-ray crystallography. In KM-12 cells harboring TPM3-NTRK1 fusion, merestinib 
exhibits potent p-NTRK1 inhibition in vitro by western blot and elicits an 
anti-proliferative response in two- and three-dimensional growth. Merestinib 
treatment demonstrated profound tumor growth inhibition in in vivo cancer models 
harboring either a TPM3-NTRK1 or an ETV6-NTRK3 gene fusion. To recapitulate 
resistance observed from type I NTRK kinase inhibitors entrectinib and 
larotrectinib, we generated NIH-3T3 cells exogenously expressing TPM3-NTRK1 
wild-type, or acquired mutations G595R and G667C in vitro and in vivo. 
Merestinib blocks tumor growth of both wild-type and mutant G667C TPM3-NTRK1 
expressing NIH-3T3 cell-derived tumors. These preclinical data support the 
clinical evaluation of merestinib, a type II NTRK kinase inhibitor 
(NCT02920996), both in treatment naïve patients and in patients progressed on 
type I NTRK kinase inhibitors with acquired secondary G667C mutation in NTRK 
fusion bearing tumors.