Stattic enhances the anti-tumor activity of AZD4547 in LUSC by blocking STAT3/RRM2-mediated DNA repair and inducing...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Fibroblast growth factor receptor (FGFR) alterations are common in lung squamous cell carcinoma (LUSC).
• FGFR inhibitors are potential therapies, but compensatory survival pathways limit their efficacy.
• STAT3 activation is a known resistance mechanism in FGFR inhibitor therapy.

Purpose of the Study:

• To evaluate a combinatorial therapy using a pan-FGFR inhibitor (AZD4547) and a STAT3 inhibitor (Stattic) for FGFR1-positive LUSC.
• To investigate the mechanisms underlying the efficacy of this dual inhibition strategy.

Main Methods:

• In vitro and in vivo studies using FGFR1-positive LUSC cell lines and xenograft models.
• Assessment of cell proliferation, apoptosis, DNA damage, and mitochondrial function.
• Analysis of signaling pathways including FGFR1, STAT3, and RRM2.

Main Results:

• AZD4547 monotherapy induced IL-6/STAT3 activation and RRM2-dependent DNA repair, limiting its effectiveness.
• Combined AZD4547 and Stattic synergistically reduced cell proliferation, colony formation, and survival, while increasing apoptosis.
• Dual inhibition disrupted the STAT3/RRM2 axis, enhanced DNA damage, and induced ROS-mediated mitochondrial dysfunction.

Conclusions:

• Concurrent blockade of FGFR1 and STAT3 is a potent therapeutic strategy for FGFR1-positive LUSC.
• This combination overcomes resistance mechanisms associated with single-agent FGFR inhibition.
• The dual inhibition approach offers a promising new avenue for LUSC treatment.