Abstract
Background
In head and neck squamous cell carcinoma (HNSCC) with human papillomavirus (HPV)-negative, deregulation of cell cycle is partly due to inactivation of p16INK4 and overexpression of cyclin D1. Here we investigated the in vitro and in vivo effects of the CDK4/6 inhibitor Palbociclib alone or combined with EGFR inhibitor Cetuximab in HNSCC.
Methods and results
CCK-8, soft agar assay, colony formation assay, wound healing assay and transwell assay, β-galactosidase assay, western blotting, and cell-derived xenografts were used to investigated the in vitro and in vivo activity of drugs. Cell viability and colony formation decreased in a dose-dependent manner in Tu686, AMC-HN8, and Fadu cells under Palbociclib treatment. Palbociclib remarkably inhibited migration, invasion and the expression MMP-9 in HNSCC cells. Palbociclib also induced senescence. Palbociclib caused the dephosphorylation of RB but increased the cyclin D1 level in a dose-dependent manner. Moreover, combination with Cetuximab could significantly prevent the induction of cyclin D1 and activation of EGFR signals from Palbociclib treatment. Nevertheless, only within the range of certain concentrations, a synergistic inhibitory effect on cell growth was observed when combined with Palbociclib and Cetuximab. Although the synergistic effect in Palbociclib/Cetuximab combined therapy was comparable to that in traditional chemotherapeutic regimens (cisplatin/Cetuximab) in Fadu tumor xenograft, the combination therapy was less active than Cetuximab monotherapy in Tu686 tumor xenograft.
Conclusion
In HPV-negative HNSCC, CDK4/6 inhibitor shows promising anti-tumor effects, which exhibits a synergistic effect when combined with EGFR inhibitor only in specific drug concentration and mouse model.
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Data availability
The data that support the conclusions of this study are obtained from the corresponding author upon reasonable request.
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Funding
This study was supported by the Medical Guidance Project of the Shanghai Science and Technology Commission [number 21Y11900300] and the National Key R&D Program of China [number 2020YFE0205500].
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Ruichen Li: Conceptualization, Methodology, Software, Formal analysis, Investigation, Visualization, Writing-Original Draft; Qi Wang: Methodology, Software, Formal analysis, Validation, Visualization, Writing-Original Draft; Yang Zhao: Investigation, Formal analysis; Yi Zhu: Conceptualization, Methodology, Supervision, Writing-Review & Editing; Xiaoshen Wang: Conceptualization, Supervision, Project administration, Funding acquisition, Writing-Review & Editing.
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Animal studies were performed on the basis of the International Animal Care and Use Committee-approved protocol (IACUC). The research was approved by the Ethics Committee of the Eye & ENT Hospital of Fudan University (approval numbers: 2019062-1).
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Li, R., Wang, Q., Zhao, Y. et al. Palbociclib inhibits the progression of head and neck cancer and improves the Cetuximab response under specific condition in vitro and in vivo. Mol Biol Rep 51, 455 (2024). https://doi.org/10.1007/s11033-024-09423-7
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DOI: https://doi.org/10.1007/s11033-024-09423-7