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Lenvatinib is an off\u2010label use option for ATC patients in many countries but an approved prescription in Japan. However, lenvatinib resistance is a substantial clinical challenge. Clinical ATC samples including lenvatinib\u2010resistant tumors are used to build patient\u2010derived cells and patient\u2010derived xenografts. High\u2010throughput drug screening and synergy analyses are performed to identify an effective combination partner for lenvatinib. Cellular functions are detected by cell senescence, apoptosis, cell cycle, cell viability and colony formation assays. CDK2 inhibition showed the significant synthetic lethality with lenvatinib via inhibiting G1\/S transition and inducing cell senescence in ATC. High expression of CDK2 is associated with lenvatinib resistance and poor clinical outcomes of ATC patients. Lenvatinib increased protein expression of CDK2 in lenvatinib\u2010resistant ATC cells. Mechanistically, lenvatinib inhibited protein degradation of CDK2 via reducing CDK2's interaction with the RACK1\u2010FBW7 complex, which is involved in ubiquitination and subsequent proteasomal degradation of CDK2. Combination of CDK2 inhibitors in clinical trials (Dinaciclib or PF\u201007104091) and lenvatinib markedly suppressed growth of xenograft tumors from the lenvatinib\u2010resistant patient. The findings support the combination therapy strategy of lenvatinib and CDK2 inhibitor for lenvatinib\u2010resistant ATC patients with high CDK2 expression.<\/jats:p>","DOI":"10.1002\/advs.202413514","type":"journal-article","created":{"date-parts":[[2024,12,24]],"date-time":"2024-12-24T03:10:21Z","timestamp":1735009821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting CDK2 Confers Vulnerability to Lenvatinib Via Driving Senescence in Anaplastic Thyroid Cancer"],"prefix":"10.1002","volume":"12","author":[{"given":"Ben","family":"Ma","sequence":"first","affiliation":[{"name":"Department of Head and Neck Surgery Fudan University Shanghai Cancer Center  Shanghai 200032 P. R. China"},{"name":"Department of Oncology Shanghai Medical College Fudan University  Shanghai 200032 P. R. 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