The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression

Yoo Young Lee, Ji Yoon Ryu, Young Jae Cho, Ju Yeon Choi, Jung Joo Choi, Chel Hun Choi, Jason K. Sa, Jae Ryoung Hwang, Jeong Won Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The FGF/FGFR signaling pathway plays a critical role in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway, in epithelial ovarian cancer (EOC) and strategies on overcoming AZD4547 resistance. Methods: The effect of AZD4547 on cell viability/migration was evaluated and in vivo experiments in intraperitoneal xenografts using EOC cells and a patient-derived xenograft (PDX) model were performed. The effect of the combination of AZD4547 with SU11274, a c-Met-specific inhibitor, FGF19-specific siRNA, or an FGFR4 inhibitor was evaluated by MTT assay. Results: AZD4547 significantly decreased cell survival and migration in drug-sensitive EOC cells but not drug-resistant cells. AZD4547 significantly decreased tumor weight in xenograft models of drug-sensitive A2780 and SKOV3ip1 cells and in a PDX with drug sensitivity but not in models with drug-resistant A2780-CP20 and SKOV3-TR cells. Furthermore, c-Met expression was high in SKOV3-TR and HeyA8-MDR cells, and co-administration of SU11274 and AZD4547 synergistically induced cell death. In addition, expressions of FGF19 and FGFR4 were high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20 cells. Conclusions: This study showed that AZD4547 has significant anti-cancer effects in drug-sensitive cells and PDX models but not in drug-resistant EOC cells. In drug-resistant cells, the expression level of c-Met or FGF19/FGFR4 may be a predictive biomarker for AZD4547 treatment response, and a combination strategy of drugs targeting c-Met or FGF19/FGFR4 together with AZD4547 may be an effective therapeutic strategy for EOC.

Original languageEnglish
Article number43
JournalCancer Cell International
Volume24
Issue number1
DOIs
Publication statusPublished - 2024 Dec

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

Keywords

  • AZD4547
  • Epithelial ovarian cancer
  • FGF19
  • FGFR4
  • Patient-derived xenograft
  • c-Met

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'The anti-tumor effects of AZD4547 on ovarian cancer cells: differential responses based on c-Met and FGF19/FGFR4 expression'. Together they form a unique fingerprint.

Cite this