组蛋白去乙酰化酶抑制剂调控p21/Cyclin E/Rb信号通路逆转乳腺癌CDK4/6抑制剂耐药的作用及机制研究

细胞周期蛋白依赖性激酶4/6抑制剂(CDK4/6i)通过阻滞细胞周期发挥抗肿瘤作用，是乳腺癌治疗新突破，但仍面临耐药这一影响患者生存的瓶颈。探索CDK4/6i耐药机制并寻找逆转耐药策略是进一步提高临床获益的关键。组蛋白去乙酰化酶抑制剂(HDACi)是表观遗传学抗肿瘤药物，验证发现其通过转录及泛素化途径上调p21表达，且p21表达下调是乳腺癌CDK4/6i耐药重要机制。据此，我们推测:HDACi可通过上调p21/Cyclin E/Rb通路阻滞细胞周期G1期向G2期过渡，从而逆转CDK4/6i耐药。本研究将利用乳腺癌细胞及类器官模型阐明HDACi通过转录及翻译后修饰调控p21/Cyclin E/Rb通路逆转CDK4/6i耐药的作用及机制，并在动物实验中验证。本研究将深化对CDK4/6i耐药机制认知并制定克服耐药的现实策略，开辟乳腺癌CDK4/6i耐药后治疗新思路，具有创新性、科学性和应用价值。

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), which exert anti-tumor effects by blocking the cell cycle, are a new breakthrough in breast cancer treatment, yet their drug resistance is a major bottleneck in affecting patient survival. Hence, the mechanism of CDK4/6i resistance should be explored and new targets for reversing drug resistance should be found to further improve clinical benefit.Histone deacetylase inhibitor (HDACi) is an epigenetic antitumor drug, which was validated to upregulate p21 expression through transcriptional and ubiquitination pathways, and the downregulation of p21 expression is an important mechanism of CDK4/6i resistance in breast cancer. Accordingly, we proposed an innovative hypothesis that HDACi could reverse CDK4/6i resistance by blocking the transition from G1 to G2 phase of the cell cycle through upregulation of the p21/Cyclin E/Rb signaling pathway.Using breast cancer organoids and cell lines, this study will elucidate the function and mechanism of HDACi in reversing CDK4/6i drug resistance by regulating the p21/Cyclin E/Rb signaling pathway through transcriptional and post-translational modifications, and validate them at the animal level.This study will deepen the knowledge of the CDK4/6i resistance mechanism, establish realistic strategies against CDK4/6i resistance , and open up new ideas for the treatment of breast cancer after CDK4/6i resistance, with innovative, scientific and application values.