Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer
Ben Ma1,2, Youzhou Sang2,3, Xiaoxue Du1,2
1Department of Head and Neck Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 24, 2024
Summary
Combining lenvatinib with a CDK2 inhibitor offers a new strategy for treating anaplastic thyroid cancer (ATC). This approach targets lenvatinib-resistant tumors by inhibiting CDK2, a key factor in resistance.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Anaplastic thyroid cancer (ATC) is highly lethal, with lenvatinib resistance posing a significant clinical challenge.
- Lenvatinib is used for ATC, but effective treatment options for resistant cases are limited.
Purpose of the Study:
- To identify effective combination therapies for lenvatinib-resistant anaplastic thyroid cancer.
- To investigate the role of CDK2 in lenvatinib resistance and explore CDK2 inhibition as a therapeutic strategy.
Main Methods:
- Patient-derived cells and xenografts from ATC were established.
- High-throughput drug screening and synergy analyses were performed.
- Cellular functions (senescence, apoptosis, cell cycle, viability) were assessed; CDK2 expression and degradation pathways were analyzed.
Main Results:
- CDK2 inhibition demonstrated synthetic lethality with lenvatinib, inhibiting cell cycle transition and inducing senescence in ATC.
- High CDK2 expression correlated with lenvatinib resistance and poor patient outcomes.
- Lenvatinib increased CDK2 protein levels by disrupting its degradation via the RACK1-FBW7 complex.
- Combination therapy with lenvatinib and CDK2 inhibitors suppressed xenograft tumor growth in resistant models.
Conclusions:
- CDK2 inhibition is a promising therapeutic strategy for lenvatinib-resistant ATC.
- Combining lenvatinib with CDK2 inhibitors may overcome resistance in patients with high CDK2 expression.
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