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Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines

  • Authors:
    • Femke Verhees
    • Imke Demers
    • Dion Legemaate
    • Robin Jacobs
    • Ann Hoeben
    • Bernd Kremer
    • Ernst-Jan Speel
  • View Affiliations / Copyright

    Affiliations: Department of Otorhinolaryngology, Head and Neck Surgery, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands, Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands, Department of Medical Oncology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
    Copyright: © Verhees et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 13
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    Published online on: January 8, 2025
       https://doi.org/10.3892/ijo.2025.5719
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Abstract

Human papillomavirus (HPV)‑positive and -negative head and neck squamous cell carcinoma (HNSCC) are often associated with activation of the phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway due to mutations or amplifications in PI3KCA, loss of PTEN or activation of receptor tyrosine kinases. In HPV‑negative tumors, CDKN2A (encoding p16 protein) inactivation or CCND1 (encoding Cyclin D1 protein) amplification frequently results in sustained cyclin‑dependent kinase (CDK) 4/6 activation. The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV‑positive and ‑negative HNSCC cell lines. Inhibitor efficacy was assessed in vitro using MTT assay and western blotting analysis. Cell cycle analysis was performed using flow cytometry and apoptosis was assessed using annexin V staining. Metabolic changes in terms of glycolysis and oxidative metabolism were measured by Seahorse XF96 extracellular Flux analysis. The results of the present study showed that both HPV‑positive and ‑negative HNSCC cell lines were sensitive to PI3Ki. In general, PI3Ki decreased PI3K/Akt/mTOR pathway activity, resulting in apoptosis, and decreased oxidative and glycolytic metabolism. The CDKi were particularly effective in blocking HPV‑negative cell line viability, showing decreased retinoblastoma expression and G1‑phase cell cycle arrest, whereas apoptosis was not induced. Thus, PI3Ki and CDKi efficiently inhibited their respective pathways and HNSCC cell viability in vitro, with the latter occurring only in HPV‑negative cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC.
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Copy and paste a formatted citation
Spandidos Publications style
Verhees F, Demers I, Legemaate D, Jacobs R, Hoeben A, Kremer B and Speel E: Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. Int J Oncol 66: 13, 2025.
APA
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., & Speel, E. (2025). Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. International Journal of Oncology, 66, 13. https://doi.org/10.3892/ijo.2025.5719
MLA
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., Speel, E."Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines". International Journal of Oncology 66.2 (2025): 13.
Chicago
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., Speel, E."Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines". International Journal of Oncology 66, no. 2 (2025): 13. https://doi.org/10.3892/ijo.2025.5719
Copy and paste a formatted citation
x
Spandidos Publications style
Verhees F, Demers I, Legemaate D, Jacobs R, Hoeben A, Kremer B and Speel E: Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. Int J Oncol 66: 13, 2025.
APA
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., & Speel, E. (2025). Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. International Journal of Oncology, 66, 13. https://doi.org/10.3892/ijo.2025.5719
MLA
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., Speel, E."Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines". International Journal of Oncology 66.2 (2025): 13.
Chicago
Verhees, F., Demers, I., Legemaate, D., Jacobs, R., Hoeben, A., Kremer, B., Speel, E."Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines". International Journal of Oncology 66, no. 2 (2025): 13. https://doi.org/10.3892/ijo.2025.5719
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