Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma
- Cancer Lett. 2024 May 11:593:216956. doi: 10.1016/j.canlet.2024.216956.
- 1. Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, 300060, China; National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China.
- 2. Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
- 3. Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
- 4. Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. Electronic address: [email protected].
- 5. Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, 300060, China; National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China; Department of Genetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China. Electronic address: [email protected].
- 6. Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China; Key Laboratory of Basic and Translational Medicine on Head & Neck Cancer, Tianjin, 300060, China; National Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin, 300060, China. Electronic address: [email protected].
Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 level negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.