Cisplatin exposure causes c-Myc-dependent resistance to CDK4/6 inhibition in HPV-negative head and neck squamous cell carcinoma.复制标题

顺铂暴露在HPV阴性的头颈部鳞状细胞癌中引起c-Myc依赖性对CDK4/6抑制的抵抗。

HPV-associated tumors usually lack mutations or deletions in cell cycle inhibitory proteins because the cell cycle machinery is disrupted by the E6 and E7 viral proteins. In contrast, tobacco-associated cancers acquire the capacity for unrestrained proliferation by a near ubiquitous loss of the tumor suppressor protein p16 (CDKN2A). p16 loss is tightly linked to smoking-related cancer and it serves as the biomarker for HPV-negative HNSCC 5,6 . In normal cells, p16 restrains the activity of the cyclin-dependent kinases 4 and 6 (CDK4/6). In HNSCC tumor cells, the loss of p16 confers CDK4/6 activity, resulting in hyperphosphorylation of the retinoblastoma protein (Rb). Thus far, there has been a distinct lack of therapies targeting the genetic alterations of HNSCC, with the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab being the only targeted agent to be approved. Cisplatin chemotherapy remains the most effective first-line agent in recurrent and metastatic disease. The epidemiologic and molecular data surrounding CDK4/6 and Rb in HNSCC suggest that CDK4/6 has promise as a therapeutic target in HNSCC.

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