BCAR3 confers resistance to cisplatin in head and neck squamous cell carcinoma by sustaining TGF-β/SMAD signaling

Cisplatin-based chemotherapy serves as a first-line therapy in advanced/metastatic head and neck squamous cell carcinoma (HNSCC). However, multiple factors confer treatment resistance, severely compromising its clinical efficacy. The purpose of this study was to determine the potential driving factors underlying this resistance and to develop a reliable combination treatment agent to overcome it. Using transcriptome analysis and clinical cohorts, breast cancer anti-estrogen resistance 3 (BCAR3) was identified as a candidate gene related to the development of intrinsic cisplatin resistance in HNSCC and was verified both in vitro and in vivo. Gene set enrichment analysis revealed that TGF-β/SMAD signaling was strongly activated in BCAR3-upregulated tumors. Western blotting and flow cytometry indicated that BCAR3 increased the phosphorylation of SMAD2 and facilitated the transcriptional activation of SMAD4, which suppressed mitochondria-derived apoptosis. Moreover, inhibition of TGF-β/SMAD signaling through treatment with galunisertib achieved synergistic efficacy with cisplatin. The above findings demonstrate that BCAR3 is a positive regulator of TGF-β/SMAD signaling-mediated intrinsic cisplatin resistance. Targeting the BCAR3/TGF-β/SMAD axis might be a promising therapeutic strategy for overcoming cisplatin resistance in HNSCC.