PDF(Pubmed)
Abstract：
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/β, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
摘要：
细胞周期蛋白依赖性激酶4和6（CDK4/6）在细胞周期和癌症发展中起关键作用。靶向CDK4/6已经证明了对乳腺癌的有希望的效果。然而,对CDK4/6抑制剂（CDK4/6i）的抗性，如palbociclib,在临床环境中仍然是一个巨大的挑战。利用高通量组合药物筛选和基因组测序，我们发现,在Palbociclib耐药的乳腺癌细胞和肿瘤中,小眼症相关转录因子(MITF)通过O-GlcNAc转移酶(OGT)通过O-GlcNAc酰化被激活.机械上,MITF在丝氨酸49上的O-GlcNAcylation增强了其与输入蛋白α/β的相互作用，从而促进它向细胞核的移位，它抑制palbociclib诱导的衰老。MITF或其O-GlcNAc化的抑制使抗性细胞对palbociclib重新敏感。此外，临床研究证实帕博西尼耐药或接受帕博西尼治疗的患者肿瘤中MITF的激活.总的来说，我们的研究阐明了调节帕博西尼耐药的机制,并为开发治疗CDK4/6i耐药乳腺癌患者的治疗方法提供了临床证据.
