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Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors

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 r...

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Autores principales: Konicek, Bruce W., Capen, Andrew R., Credille, Kelly M., Ebert, Philip J., Falcon, Beverly L., Heady, Gary L., Patel, Bharvin K.R., Peek, Victoria L., Stephens, Jennifer R., Stewart, Julie A., Stout, Stephanie L., Timm, David E., Um, Suzane L., Willard, Melinda D., Wulur, Isabella H., Zeng, Yi, Wang, Yong, Walgren, Richard A., Betty Yan, Sau-Chi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862616/
https://www.ncbi.nlm.nih.gov/pubmed/29568395
http://dx.doi.org/10.18632/oncotarget.24488
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author Konicek, Bruce W.
Capen, Andrew R.
Credille, Kelly M.
Ebert, Philip J.
Falcon, Beverly L.
Heady, Gary L.
Patel, Bharvin K.R.
Peek, Victoria L.
Stephens, Jennifer R.
Stewart, Julie A.
Stout, Stephanie L.
Timm, David E.
Um, Suzane L.
Willard, Melinda D.
Wulur, Isabella H.
Zeng, Yi
Wang, Yong
Walgren, Richard A.
Betty Yan, Sau-Chi
author_facet Konicek, Bruce W.
Capen, Andrew R.
Credille, Kelly M.
Ebert, Philip J.
Falcon, Beverly L.
Heady, Gary L.
Patel, Bharvin K.R.
Peek, Victoria L.
Stephens, Jennifer R.
Stewart, Julie A.
Stout, Stephanie L.
Timm, David E.
Um, Suzane L.
Willard, Melinda D.
Wulur, Isabella H.
Zeng, Yi
Wang, Yong
Walgren, Richard A.
Betty Yan, Sau-Chi
author_sort Konicek, Bruce W.
collection PubMed
description 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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spelling pubmed-58626162018-03-22 Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors Konicek, Bruce W. Capen, Andrew R. Credille, Kelly M. Ebert, Philip J. Falcon, Beverly L. Heady, Gary L. Patel, Bharvin K.R. Peek, Victoria L. Stephens, Jennifer R. Stewart, Julie A. Stout, Stephanie L. Timm, David E. Um, Suzane L. Willard, Melinda D. Wulur, Isabella H. Zeng, Yi Wang, Yong Walgren, Richard A. Betty Yan, Sau-Chi Oncotarget Research Paper 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. Impact Journals LLC 2018-02-13 /pmc/articles/PMC5862616/ /pubmed/29568395 http://dx.doi.org/10.18632/oncotarget.24488 Text en Copyright: © 2018 Konicek et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Konicek, Bruce W.
Capen, Andrew R.
Credille, Kelly M.
Ebert, Philip J.
Falcon, Beverly L.
Heady, Gary L.
Patel, Bharvin K.R.
Peek, Victoria L.
Stephens, Jennifer R.
Stewart, Julie A.
Stout, Stephanie L.
Timm, David E.
Um, Suzane L.
Willard, Melinda D.
Wulur, Isabella H.
Zeng, Yi
Wang, Yong
Walgren, Richard A.
Betty Yan, Sau-Chi
Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title_full Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title_fullStr Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title_full_unstemmed Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title_short Merestinib (LY2801653) inhibits neurotrophic receptor kinase (NTRK) and suppresses growth of NTRK fusion bearing tumors
title_sort merestinib (ly2801653) inhibits neurotrophic receptor kinase (ntrk) and suppresses growth of ntrk fusion bearing tumors
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862616/
https://www.ncbi.nlm.nih.gov/pubmed/29568395
http://dx.doi.org/10.18632/oncotarget.24488
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