Fedratinib reveals chemotherapeutic potential in esophageal squamous cell cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Drug repurposing is a key strategy for novel anticancer drug discovery.
• Fedratinib, a Janus kinase 2 (JAK2) inhibitor, is approved for myelofibrosis.
• This study investigates fedratinib's potential against esophageal squamous cell carcinoma (ESCC).

Purpose of the Study:

• To evaluate the antitumor efficacy of fedratinib in esophageal squamous cell carcinoma (ESCC).
• To elucidate the underlying mechanisms of fedratinib's action in ESCC.
• To validate fedratinib's efficacy across diverse preclinical models.

Main Methods:

• Utilized ESCC cell lines (Eca109, KYSE150) for in vitro studies assessing proliferation, migration, apoptosis, and cell cycle.
• Employed RT-qPCR and Western blot to analyze molecular changes.
• Validated antitumor effects in vivo using xenograft models and patient-derived organoid (PDO) models.
• Investigated mechanisms through STAT3 overexpression and functional rescue experiments.

Main Results:

• Fedratinib significantly inhibited ESCC cell proliferation and migration, induced G2/M phase cell cycle arrest, and promoted apoptosis in vitro.
• Demonstrated suppressed tumor growth in xenograft models and consistent efficacy in ESCC PDOs.
• Revealed inhibition of JAK2/STAT3 signaling pathway activation and downregulation of vimentin, survivin, and cyclin D1.
• STAT3, vimentin, survivin, or cyclin D1 overexpression partially reversed fedratinib's effects.

Conclusions:

• Fedratinib exhibits significant antitumor effects against ESCC in vitro, in vivo, and in PDO models.
• The mechanism involves the suppression of the JAK2-STAT3 signaling axis and its downstream targets.
• Fedratinib represents a promising repurposed therapeutic agent for esophageal squamous cell carcinoma.