GZD824 overcomes FGFR1-V561F/M mutant resistance in vitro and in vivo

Cancer Med. 2021 Jul;10(14):4874-4884. doi: 10.1002/cam4.4041. Epub 2021 Jun 10.

Abstract

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 IC50 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 (IC50 :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.

Keywords: FGFR1; GZD824; V561F; resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Benzamides / pharmacology*
  • Cell Line
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Drug Screening Assays, Antitumor
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, SCID
  • Morpholines / pharmacology
  • Mutation*
  • Neoplasm Transplantation
  • Phenylurea Compounds / pharmacology
  • Phosphorylation / drug effects
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology
  • Pyrroles / pharmacology
  • Quinoxalines / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
  • Receptor, Fibroblast Growth Factor, Type 1 / genetics*
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism
  • Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors

Substances

  • Antineoplastic Agents
  • Benzamides
  • Morpholines
  • Phenylurea Compounds
  • Pyrazoles
  • Pyrimidines
  • Pyrroles
  • Quinoxalines
  • futibatinib
  • erdafitinib
  • infigratinib
  • FGFR1 protein, human
  • FGFR2 protein, human
  • FGFR3 protein, human
  • FGFR4 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptor, Fibroblast Growth Factor, Type 2
  • Receptor, Fibroblast Growth Factor, Type 3
  • Receptor, Fibroblast Growth Factor, Type 4
  • olverembatinib
  • pemigatinib