Open AccessGZD824 overcomes FGFR1‐V561F/M mutant resistance in vitro and in vivo
Author(s) -
Jiang Kaili,
Tang Xia,
Guo Jing,
He Rui,
Chan Shingpan,
Song Xiaojuan,
Tu Zhengchao,
Wang Yuting,
Ren Xiaomei,
Ding Ke,
Zhang Zhang
Publication year - 2021
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.4041
Subject(s) - fibroblast growth factor receptor 1 , in vivo , mutant , in vitro , fibroblast growth factor receptor , ic50 , cancer research , fibroblast growth factor , chemistry , medicine , biology , biochemistry , genetics , receptor , gene
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.