Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, China.
Nat Commun. 2021 Sep 10;12(1):5386. doi: 10.1038/s41467-021-25700-6.
Although inhibitors targeting CDK4/6 kinases (CDK4/6i) have shown promising clinical prospect in treating ER+/HER2- breast cancers, acquired drug resistance is frequently observed and mechanistic knowledge is needed to harness their full clinical potential. Here, we report that inhibition of CDK4/6 promotes βTrCP1-mediated ubiquitination and proteasomal degradation of RB1, and facilitates SP1-mediated CDK6 transcriptional activation. Intriguingly, suppression of CK1ε not only efficiently prevents RB1 from degradation, but also prevents CDK4/6i-induced CDK6 upregulation by modulating SP1 protein stability, thereby enhancing CDK4/6i efficacy and overcoming resistance to CDK4/6i in vitro. Using xenograft and PDX models, we further demonstrate that combined inhibition of CK1ε and CDK4/6 results in marked suppression of tumor growth in vivo. Altogether, these results uncover the molecular mechanisms by which CDK4/6i treatment alters RB1 and CDK6 protein abundance, thereby driving the acquisition of CDK4/6i resistance. Importantly, we identify CK1ε as an effective target for potentiating the therapeutic efficacy of CDK4/6 inhibitors.
虽然靶向 CDK4/6 激酶的抑制剂（CDK4/6i）在治疗 ER+/HER2- 乳腺癌方面显示出了有前景的临床前景，但经常观察到获得性药物耐药性，需要机制知识来充分发挥其临床潜力。在这里，我们报告 CDK4/6 的抑制作用促进了 βTrCP1 介导的 RB1 的泛素化和蛋白酶体降解，并促进了 SP1 介导的 CDK6 的转录激活。有趣的是，抑制 CK1ε 不仅能有效地阻止 RB1 的降解，还能通过调节 SP1 蛋白稳定性来阻止 CDK4/6i 诱导的 CDK6 上调，从而增强 CDK4/6i 的疗效并克服体外对 CDK4/6i 的耐药性。通过异种移植和 PDX 模型，我们进一步证明了 CK1ε 和 CDK4/6 的联合抑制在体内显著抑制了肿瘤生长。总之，这些结果揭示了 CDK4/6i 治疗如何改变 RB1 和 CDK6 蛋白丰度从而导致 CDK4/6i 耐药性的分子机制。重要的是，我们确定 CK1ε 是增强 CDK4/6 抑制剂治疗效果的有效靶点。
