Regulation of resistance to CDK4/6 inhibitor in breast cancer

项目摘要 细胞周期蛋白依赖性激酶CDK4/6抑制剂(CDK4/6I)与芳香化酶抑制剂联合应用是一线药物 ER阳性晚期或转移性乳腺癌的治疗。尽管CDK4/6抑制剂显著改善 这类患者的总体存活率，并不是所有患者对这些药物都有反应，而大多数患者的肿瘤 最初对CDK4/6i的反应最终发展为获得性耐药。尽管已经投入了很多努力 在耐药机制的研究中，CDK4/6I耐药仍然是HR+乳腺癌面临的一大挑战。 因此，迫切需要开发新的方法来克服对CDK4/6I耐药的乳腺癌的耐药性。 (CRBC)。O-连接-N-乙酰氨基葡萄糖基化(O-GlcN-酰化)是糖基化的一种类型，当 单糖O-GlcNAc通过O-GlcNAc转移酶添加到蛋白质的丝氨酸或苏氨酸残基上 (OGT)。O-GlcN酰化参与了一系列细胞活动，而异常的O-GlcN酰化 与包括癌症在内的多种疾病有牵连。然而，O-GlcN酰化在抗癌药物中的作用 阻力在很大程度上仍不为人所知。 通过创新的定量高通量组合筛查(QHTCS)和后续 利用细胞和分子方法进行了广泛的初步研究，我们发现了一种新的OGT介导的 ER+乳腺癌对CDK4/6I耐药的调控机制这项提议的主要目标是 探讨OGT途径在调节CRBC细胞对CDK4/6I耐药中的作用。 具体地说，我们将(1)研究OGT介导的途径如何调节的分子机制 CDK4/6I在CRBC细胞中的耐药性，(2)评估新发现的药物联合治疗对CRBC细胞的影响 使用耐药的PDX和同基因模型进行帕波西利耐药，(3)进行临床研究以进一步评估 OGT途径与肿瘤患者CDK4/6I耐药的相关性研究这个 拟议研究的完成不仅将阐明调控CDK4/6I耐药性的新机制 ER+乳腺癌，也为CRBC患者提供了一种创新的治疗策略。

Project Summary Cyclin-dependent kinase CDK4/6 inhibitor (CDK4/6i) in combination with aromatase inhibitors is the first-line treatment for ER+ advanced or metastatic breast cancer. Despite CDK4/6 inhibitors significantly improve overall survival of such patients, not all patients respond to these drugs and most patients whose tumors initially respond to CDK4/6i eventually develop acquired resistance. Although many efforts have been invested into the studying mechanism of resistance, CDK4/6i resistance remains a big challenge for HR+ breast cancer. Thus, it is urgent to develop new approaches to overcome resistance in CDK4/6i resistant breast cancer (CRBC). O-linked-N-acetylglucosaminylation (O-GlcNAcylation) is one type of glycosylation that occurs when a monosaccharide, O-GlcNAc, is added onto serine or threonine residues of proteins by O-GlcNAc transferase (OGT). O-GlcNAcylation is involved in a range of cellular activities and aberrant O-GlcNAcylation has been implicated in a host of diseases including cancer. However, the role of O-GlcNAcylation in cancer drug resistance remains largely unknown. Through an innovative quantitative high throughput combination screen (qHTCS) and follow-up extensive preliminary studies using cellular and molecular approaches, we identified a novel OGT-mediated mechanism regulating the resistance to CDK4/6i in ER+ breast cancer. The major objective of this proposal is to determine the role of OGT-mediated pathway in the regulation of CDK4/6i resistance in CRBC cells. Specifically, we will (1) investigate the molecular mechanism of how OGT-mediated pathway regulates CDK4/6i resistance in CRBC cells, (2) evaluate the effects of newly identified drug combinational treatments on palbociclib resistance using resistant PDX and syngeneic models, (3) conduct clinical study to further evaluate the correlation between OGT-mediated pathway and CDK4/6i resistance in tumors from patients. The completion of proposed studies will not only elucidate a novel mechanism regulating CDK4/6i resistance in ER+ breast cancer, but also provide an innovative therapeutic strategy to treat CRBC patients.