准独特的连接体结合域结构特征降低了Y537S ESR1突变乳腺癌细胞中的DKK1的调节
K S Young1, G R Hancock1, E C Fink1
1Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, 50153, USA.
Breast cancer research : BCR
|January 17, 2025
概括
一种新型药物,T6I-29,对具有常见突变的雌激素受体阳性乳腺癌显示出前途. 这种选择性雌激素受体调节器 (SERM) 针对内分泌疗法耐药性,并降低DKK1,这是一种涉及癌症生长的蛋白质.
科学领域:
- 内分泌学 在内分泌学.
- 在瘤学瘤学.
- 分子生物学分子生物学
背景情况:
- 内分泌疗法耐药性是乳腺癌治疗的一个主要挑战.
- 雌激素受体α (ERα) 的突变,特别是Y537S,使其对标准疗法产生抗性.
- 下一代选择性雌激素受体调节剂 (SERM) 和降解剂/降低调节剂 (SERD) 提供潜在的,但往往没有持久的反应.
研究的目的:
- 综合评估新型SERM,T6I-29对具有Y537S ERα突变的乳腺癌细胞的活性.
- 阐明T6I-29在抗内分泌抵抗性乳腺癌的疗效背后的分子机制.
- 为了确定与T6I-29治疗相关的潜在新治疗点.
主要方法:
- 进行结构生物化学分析.
- 在体外基于细胞的试验.
- 在体内临床前模型.
- RNA测序用于评估基因表达变化.
主要成果:
- T6I-29在Y537S ERα乳腺癌细胞中显示出显著的抗增殖活性.
- T6I-29治疗导致DKK1的新型下调,DKK1是一种具有已知的致癌作用的糖蛋白.
- 与健康对照组相比,DKK1在ER阳性乳腺癌患者的血中被发现是显著丰富的.
结论:
- T6I-29是对Y537S ERα突变乳腺癌的有效药物,提供了一种新的治疗策略.
- T6I-29对DKK1的下调代表了一种新的作用机制和潜在的治疗途径.
- 这项研究强调了新型SERM和SERD在克服内分泌抵抗方面的潜力,并确定了DKK1作为生物标志物和治疗点.
更多相关视频
11:32Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
Published on: March 27, 2020
6.7K
08:11Characterization of Cell Membrane Extensions and Studying Their Roles in Cancer Cell Adhesion Dynamics
Published on: March 26, 2018
8.1K
相关概念视频
01:49Conserved Binding Sites
4.2K
Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
4.2K
01:27Transducer Mechanism: Enzyme-Linked Receptors
2.3K
Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
Major types that are helpful drug targets include:
2.3K
02:40Ligand Binding Sites
12.7K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
12.7K
01:26Receptor Tyrosine Kinases
12.2K
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
12.2K
00:49Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
02:38Mitogens and the Cell Cycle
6.4K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.4K