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Updated: Sep 17, 2025

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Heterogeneous c-Met Activation in Osteosarcoma Dictates Synergistic Vulnerability to Combined c-Met Inhibition and

Guidong Li1, Hiroyuki Kawashima2, Taro Sasaki2

  • 1Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, P.R. China azumatakafumi@163.com.

Anticancer Research
|June 27, 2025
PubMed
Abstract

Insights

Combining c-Met inhibitor PHA665752 with methotrexate (MTX) shows synergistic cytotoxicity in osteosarcoma (OS) cells. This dual approach targets overlapping pathways to enhance OS treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osteosarcoma (OS) treatment faces challenges due to chemoresistance and toxicity.
  • Aberrant c-Met signaling is implicated in OS progression, but monotherapy with c-Met inhibitors is often limited by resistance.
  • Methotrexate (MTX), a standard OS chemotherapeutic, interacts with c-Met signaling pathways.

Purpose of the Study:

  • Investigate mechanisms of HGF/c-Met signaling activation in OS cells.
  • Evaluate the synergistic cytotoxicity of the c-Met inhibitor PHA665752 combined with MTX.
  • Explore potential therapeutic strategies for overcoming chemoresistance in OS.

Main Methods:

  • Analyzed MET/HGF expression in six OS cell lines using qRT-PCR and western blot.
  • Assessed c-Met activation mechanisms via HGF stimulation and neutralization experiments.
  • Evaluated drug sensitivity and combination efficacy using MTS assays and Chou-Talalay synergy analysis.

Main Results:

  • OS cell lines exhibited heterogeneous c-Met activation patterns.
  • PHA665752 suppressed c-Met signaling and induced apoptosis; MTX showed differential potency.
  • Synergistic cytotoxicity was observed with PHA665752 and MTX combinations in specific OS cell lines and treatment schedules.

Conclusions:

  • PHA665752 combined with MTX synergistically inhibits OS cell growth.
  • The combination therapy achieves dual suppression of c-Met signaling and MTX-mediated cytotoxicity.
  • Co-targeting overlapping pathways presents a promising strategy to enhance OS treatment efficacy.
Keywords:
Osteosarcomaapoptosis combination therapyc-Met inhibitorsmethotrexatesignaling pathwayssynergy

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