2. Academic Validation
  3. Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma

Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma

  • Cell Death Dis. 2020 Oct 28;11(10):925. doi: 10.1038/s41419-020-03126-0.
Qinchao Hu 1 2,  Jianmin Peng 1 2,  Laibo Jiang 1 2,  Wuguo Li 3,  Qiao Su 3,  Jiayu Zhang 1 2,  Huan Li 4 5,  Ming Song 4 6,  Bin Cheng 7 8,  Juan Xia 9 10,  Tong Wu 11 12
Affiliations

Affiliations

  • 1 Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.
  • 3 Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
  • 5 Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 Department of Head and Neck Surgery, Sun Yat‑sen University Cancer Center, Guangzhou, China.
  • 7 Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China. chengbin@mail.sysu.edu.cn.
  • 8 Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China. chengbin@mail.sysu.edu.cn.
  • 9 Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China. xiajuan@mail.sysu.edu.cn.
  • 10 Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China. xiajuan@mail.sysu.edu.cn.
  • 11 Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China. wutong23@mail.sysu.edu.cn.
  • 12 Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China. wutong23@mail.sysu.edu.cn.
PMID: 33116117 DOI: 10.1038/s41419-020-03126-0
Abstract

CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on Cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the Anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated β-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and STAT3 pathways. The LY2835219-induced SASP resulted in upregulation of Cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the Anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16297A
    99.96%, CDK4/6抑制剂
    CDK
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