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GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo
Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors ha...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290231/ https://www.ncbi.nlm.nih.gov/pubmed/34114373 http://dx.doi.org/10.1002/cam4.4041 |
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author | Jiang, Kaili Tang, Xia Guo, Jing He, Rui Chan, Shingpan Song, Xiaojuan Tu, Zhengchao Wang, Yuting Ren, Xiaomei Ding, Ke Zhang, Zhang |
author_facet | Jiang, Kaili Tang, Xia Guo, Jing He, Rui Chan, Shingpan Song, Xiaojuan Tu, Zhengchao Wang, Yuting Ren, Xiaomei Ding, Ke Zhang, Zhang |
author_sort | Jiang, Kaili |
collection | PubMed |
description | Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC(50) value of 4.14 ± 0.96, 2.77 ± 0.082, and 8.10 ± 0.15 nmol/L. It effectively overcomes FGFR1‐V561F/M and other mutantresistance in Ba/F3 stable cells (IC(50):8.1–55.0 nM), and effectively inhibits the growth of Ba/F3‐FGFR1‐V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials. |
format | Online Article Text |
id | pubmed-8290231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82902312021-07-21 GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo Jiang, Kaili Tang, Xia Guo, Jing He, Rui Chan, Shingpan Song, Xiaojuan Tu, Zhengchao Wang, Yuting Ren, Xiaomei Ding, Ke Zhang, Zhang Cancer Med Cancer Biology Abnormallyactivated FGFR1 has been validated as a therapeutic target for differentcancers. Although a variety of FGFR inhibitors have shown benefit in manyclinical patients with FGFR1 aberration, FGFR1 mutant resistance such as V561Mmutation, has been reported. To date however, no FGFR inhibitors have beenapproved to treat patients with FGFR mutant resistance. Herein, we report that GZD824, athird generation ABL inhibitor (Phase II, China), overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo. GZD824potently suppresses FGFR1/2/3 with an IC(50) value of 4.14 ± 0.96, 2.77 ± 0.082, and 8.10 ± 0.15 nmol/L. It effectively overcomes FGFR1‐V561F/M and other mutantresistance in Ba/F3 stable cells (IC(50):8.1–55.0 nM), and effectively inhibits the growth of Ba/F3‐FGFR1‐V561F/M mutantxenograft tumors in vivo (TGI=73.4%, 49.8% at20mg/kg, p.o, q2d). GZD824may be considered to be an effective drug to treat patients with FGFR1 abnormalactivation or mutant resistance in clinical trials. John Wiley and Sons Inc. 2021-06-10 /pmc/articles/PMC8290231/ /pubmed/34114373 http://dx.doi.org/10.1002/cam4.4041 Text en © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Biology Jiang, Kaili Tang, Xia Guo, Jing He, Rui Chan, Shingpan Song, Xiaojuan Tu, Zhengchao Wang, Yuting Ren, Xiaomei Ding, Ke Zhang, Zhang GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title | GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title_full | GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title_fullStr | GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title_full_unstemmed | GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title_short | GZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo |
title_sort | gzd824 overcomes fgfr1‐v561f/m mutant resistance in vitro and in vivo |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290231/ https://www.ncbi.nlm.nih.gov/pubmed/34114373 http://dx.doi.org/10.1002/cam4.4041 |
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