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

Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LUSC) and represent potential targets for therapy with FGFR inhibitors. However, FGFR inhibitor monotherapy is often undermined by compensatory survival pathways. In this study, a combinatorial therapeutic approach using the STAT3 inhibitor Stattic together with the pan-FGFR inhibitor AZD4547 for FGFR1-positive LUSC were assessed. The results showed that AZD4547 suppresses FGFR1 phosphorylation, triggers IL-6/STAT3 activation and induces RRM2-dependent DNA repair, limiting single-agent efficacy. Combining AZD4547 with the STAT3 inhibitor Stattic synergistically impaired cell proliferation, colony formation, and survival, and markedly enhanced apoptosis in vitro and in vivo. Mechanistically, dual inhibition disrupted the STAT3/RRM2 axis, promoting DNA damage and simultaneously provoking ROS-induced mitochondrial dysfunction. These findings nominate concurrent FGFR1 and STAT3 blockade as a promising therapeutic approach for FGFR1-positive lung squamous cell carcinomas.