Repurposing of c-MET Inhibitor Tivantinib Inhibits Pediatric Neuroblastoma Cellular Growth

Area of Science:

• Oncology
• Molecular Biology
• Pediatric Cancer Research

Background:

• Dysregulated c-MET receptor tyrosine kinase signaling drives oncogenesis in various cancers.
• Pediatric neuroblastoma (NB) is an aggressive extracranial solid tumor with poor long-term survival rates.
• High c-MET expression is linked to aggressive tumor behavior and poor prognosis in NB.

Purpose of the Study:

• To investigate the correlation between MET expression and NB patient outcomes.
• To evaluate the therapeutic potential of c-MET inhibition in NB.
• To elucidate the mechanisms by which c-MET affects NB cell growth and signaling.

Main Methods:

• Analysis of a large cohort of primary NB patient data.
• In vitro studies using NB cell lines (MYCN-amplified and non-amplified).
• Treatment with tivantinib, a small molecule c-MET inhibitor.
• Assessment of cell proliferation, 3D spheroid formation, cell cycle progression, apoptosis, and signaling pathway modulation.

Main Results:

• High MET expression significantly correlates with reduced overall survival, disease progression, and relapse in NB patients.
• Tivantinib effectively inhibits NB cell proliferation and 3D spheroid growth, irrespective of MYCN amplification status.
• c-MET inhibition by tivantinib induces G2/M cell cycle arrest and apoptosis, while suppressing PI3K, STAT, and Ras signaling pathways.

Conclusions:

• c-MET signaling is a key regulator of NB tumor growth and progression.
• Tivantinib demonstrates significant anti-tumor activity against NB, highlighting its potential as a therapeutic agent.
• Targeting c-MET, potentially in combination with existing therapies, offers a promising strategy for treating high-risk NB and other c-MET-driven cancers.