Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer

Anaplastic thyroid cancer (ATC) is the deadliest malignancy originating from thyroid follicular epithelium. While lenvatinib is an off-label treatment option for ATC patients in many countries, it is an approved prescription in Japan. However, resistance to lenvatinib poses a significant clinical challenge. To study this, clinical ATC samples, including those from lenvatinib-resistant tumors, are used to create patient-derived cells and xenograft models. High-throughput drug screening and synergy analyses are conducted to identify effective combination therapies. Cellular functions, including senescence, apoptosis, cell cycle progression, viability, and colony formation, are assessed. Inhibition of CDK2 was found to induce synthetic lethality when combined with lenvatinib, by blocking the G1/S transition and promoting cell senescence in ATC. Elevated expression of CDK2 correlates with lenvatinib resistance and poor clinical outcomes in ATC patients. Lenvatinib treatment increased CDK2 protein levels in resistant ATC cells. Mechanistically, lenvatinib prevents the degradation of CDK2 by reducing its interaction with the RACK1-FBW7 complex, which is involved in CDK2′s ubiquitination and proteasomal degradation. The combination of lenvatinib and CDK2 inhibitors currently in clinical trials (Dinaciclib or PF-07104091) significantly suppressed the growth of xenograft tumors from lenvatinib-resistant patients. These findings suggest that combining lenvatinib with CDK2 inhibitors could be an effective therapeutic strategy for ATC patients exhibiting high CDK2 expression and lenvatinib resistance.