Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
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Bruce W. Konicek1, Andrew R. Capen1, Kelly M. Credille1, Philip J. Ebert1, Beverly L. Falcon1, Gary L. Heady1, Bharvin K.R. Patel1, Victoria L. Peek1, Jennifer R. Stephens1, Julie A. Stewart1, Stephanie L. Stout1, David E. Timm1, Suzane L. Um1, Melinda D. Willard1, Isabella H. Wulur1, Yi Zeng1, Yong Wang1, Richard A. Walgren1 and Sau-Chi Betty Yan1
1Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
Bruce W. Konicek, email: [email protected]
Keywords: NTRK fusion; merestinib; LY2801653; NTRK inhibitor; type II kinase inhibitor
Received: October 19, 2017 Accepted: January 31, 2018 Published: February 13, 2018
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.
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