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Background <p>Precisi on medicine is an emerging approach for disease treatment and its major challenge is the development of drug resistance. Understanding the role of specific mutations in drug resistance is crucial for the development of next-generation therapeutics.</p> Methodology <p>Cyclin-dependent kinase-4 (CDK4) is a pivotal regulator of the cell cycle, with mutations implicated in oncogenesis in oral squamous cell carcinoma (OSCC). Abemaciclib is one of the major reference drugs designed to inhibit CDK4. This study employs a biophysical approach to examine the binding dynamics between abemaciclib, a selective CDK4 inhibitor, and both wild-type and mutant forms of CDK4. Focusing on the hinge loop region, which includes mutations D99G, R101M, T102K, and P110L, molecular dynamics simulations reveal differential effects on drug binding stability.</p> Results <p>Findings indicate that while D99G and R101M mutants sustain stable drug interactions, the T102K and P110L mutants exhibit significantly weakened binding, evidenced by altered free energy landscapes, increased structural fluctuations, and diminished hydrogen bond interactions. These findings suggest that patients with CDK4 mutations, particularly T102K and P110L, may exhibit resistance to abemaciclib, necessitating the development of alternative therapeutic strategies.</p> Conclusion <p>Further studies are essentially required to enhance the precision of cancer treatment, ensuring that each patient receives the most effective therapy based on their unique genetic makeup.</p>

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Deciphering the differential impact of CDK4 mutations on abemaciclib binding in oral squamous cell carcinoma: a precision medicine approach

  • 期刊论文

  • 发表日期：

    2025年7月21日

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  • Yu Huang,
  • Mi Zhang,
  • Yi Ni

摘要

Background

Precisi on medicine is an emerging approach for disease treatment and its major challenge is the development of drug resistance. Understanding the role of specific mutations in drug resistance is crucial for the development of next-generation therapeutics.

Methodology

Cyclin-dependent kinase-4 (CDK4) is a pivotal regulator of the cell cycle, with mutations implicated in oncogenesis in oral squamous cell carcinoma (OSCC). Abemaciclib is one of the major reference drugs designed to inhibit CDK4. This study employs a biophysical approach to examine the binding dynamics between abemaciclib, a selective CDK4 inhibitor, and both wild-type and mutant forms of CDK4. Focusing on the hinge loop region, which includes mutations D99G, R101M, T102K, and P110L, molecular dynamics simulations reveal differential effects on drug binding stability.

Results

Findings indicate that while D99G and R101M mutants sustain stable drug interactions, the T102K and P110L mutants exhibit significantly weakened binding, evidenced by altered free energy landscapes, increased structural fluctuations, and diminished hydrogen bond interactions. These findings suggest that patients with CDK4 mutations, particularly T102K and P110L, may exhibit resistance to abemaciclib, necessitating the development of alternative therapeutic strategies.

Conclusion

Further studies are essentially required to enhance the precision of cancer treatment, ensuring that each patient receives the most effective therapy based on their unique genetic makeup.