Dual targeting CDK4/6 and CDK7 augments tumor response and anti-tumor immunity in breast cancer

CDK4/6 inhibitors (CDK4/6i) have significantly improved the prognosis for hormone-positive (HR+) breast cancer patients. However, the emergence of drug resistance severely limits their long-term efficacy, and CDK4/6i monotherapy remains largely ineffective against triple-negative breast cancer (TNBC). Here, we demonstrate that combining CDK4/6i with CDK7 inhibitors (CDK7i) offers a promising therapeutic strategy to overcome resistance in both HR+ breast cancer and TNBC. Kinetic analyses reveal that CDK7i primarily targets RNA polymerase II-mediated transcription, a key driver of CDK4/6i resistance by amplifying E2F activity following the degradation of the retinoblastoma protein. Consequently, the combination of CDK4/6i and CDK7i synergistically suppresses E2F activity and inhibits the growth of drug-resistant tumors. Furthermore, this combination stimulates immune response pathways and cytokine production in cancer cells, enhancing anti-tumor immunity. These findings provide critical insights into evolving CDK inhibition strategies and highlight the therapeutic application of CDK7i in breast cancer management. Bulk RNA-Seq was performed on the MDA-MB-231 cell line, and scRNA-Seq was conducted on tumors extracted from an AT3-OVA syngeneic mouse model.

细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）已显著改善激素受体阳性（HR+）乳腺癌患者的预后。然而，耐药性的出现严重制约了其长期临床疗效，且CDK4/6i单药治疗对三阴性乳腺癌（TNBC）基本无效。本研究证实，将CDK4/6i与CDK7抑制剂（CDK7i）联合使用，可为克服HR+乳腺癌及三阴性乳腺癌的耐药性提供极具前景的治疗策略。动力学分析结果显示，CDK7i主要靶向RNA聚合酶II介导的转录过程——该过程可在视网膜母细胞瘤蛋白降解后通过扩增E2F活性，成为CDK4/6i耐药的关键驱动因素。因此，CDK4/6i与CDK7i的联合用药可协同抑制E2F活性，并阻滞耐药肿瘤的生长。此外，该联合方案还可激活癌细胞内的免疫应答通路与细胞因子产生过程，增强抗肿瘤免疫能力。本研究结果为优化CDK抑制类治疗策略提供了关键理论依据，并凸显了CDK7i在乳腺癌临床管理中的应用价值。本研究对MDA-MB-231细胞系开展了批量RNA测序（Bulk RNA-Seq），并对AT3-OVA同源基因小鼠模型提取的肿瘤组织实施了单细胞RNA测序（scRNA-Seq）。