AKT1与DHX9相互作用,以减轻卵巢癌中R循环诱导的复制压力
Tzu-Ting Huang1, Chih-Yuan Chiang2, Jayakumar R Nair1
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
Cancer research
|January 19, 2024
概括
一种ATR和AKT抑制剂的组合有效地治疗抗PARP抑制剂的卵巢癌. 该策略针对DNA损伤和复制压力,为BRCA突变高度血清卵巢癌提供了一种新的治疗方法.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 高度血清性卵巢癌 (HGSOC) 具有PARP抑制剂 (PARPi) 耐药的BRCA突变 (BRCAm) 是一个重大的临床挑战.
- 现有的治疗方法在这种耐药亚型中有效性有限.
研究的目的:
- 为了确定有效的治疗策略,对PARPi敏感和PARPi抗性BRCAm HGSOC.
- 阐明新药组合的潜在分子机制.
主要方法:
- 定量高通量药物组合查.
- 评估DNA损伤和R循环介导的复制应激诱导.
- 研究AKT1-DHX9相互作用及其在R循环解析中的作用.
主要成果:
- 一种ATR抑制剂 (ATRi) 和一种AKT抑制剂 (AKTi) 的组合在对PARPi敏感和耐药BRCAm HGSOC.中都表现出有效性.
- 这种组合会诱导DNA损伤和R循环介导的复制应激.
- AKT 抑制剂 (AKTi) 通过调节 DHX9 招募到 R 循环来增强 ATR 抑制剂 (ATRi) 诱导的复制应激.
- DHX9的上调及其与AKT1的联合表达与PARPi抗性HGSOC中较差的存活率相关.
结论:
- ATRi和AKTi的组合是BRCAm HGSOC的合理和有效的治疗策略,无论PARPi的耐药性如何.
- 针对AKT1-DHX9相互作用提供了一种新的方法来克服卵巢癌中PARPi抵抗.
相关概念视频
02:37Restarting Stalled Replication Forks
5.8K
DNA replication is initiated at sites containing predefined DNA sequences known as origins of replication. DNA is unwound at these sites by the minichromosome maintenance (MCM) helicase and other factors such as Cdc45 and the associated GINS complex.The unwound single strands are protected by replication protein A (RPA) until DNA polymerase starts synthesizing DNA at the 5’ end of the strand in the same direction as the replication fork. To prevent the replication fork from falling apart,...
5.8K
02:37DNA Damage can Stall the Cell Cycle
9.2K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.2K
01:02The DNA Replication Fork
36.0K
An organism’s genome needs to be duplicated in an efficient and error-free manner for its growth and survival. The replication fork is a Y-shaped active region where two strands of DNA are separated and replicated continuously. The coupling of DNA unzipping and complementary strand synthesis is a characteristic feature of a replication fork. Organisms with small circular DNA, such as E. coli, often have a single origin of replication; therefore, they have only two replication...
36.0K
00:55DNA Helicases
21.3K
DNA unwinding helicase enzymes are a type of motor protein. Motor proteins can translocate along filaments or polymers using energy generated from ATP hydrolysis. Helicases are involved in all the important cellular processes where DNA unwinding is required, such as DNA replication, repair, recombination, and transcription. They are present in all living organisms, but vary in their structure, function, and mechanism of action. For example, in prokaryotes, DnaB helicase binds and translocates...
21.3K
02:31Homologous Recombination
50.6K
The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
50.6K
02:38S-Cdk Initiates DNA Replication
4.7K
The cell cycle is a series of events leading to DNA duplication followed by the division of cell content to form two daughter cells. The cell cycle progresses in four stages—the cell increases in size (gap 1 or G1-phase), duplicates its DNA (synthesis or S-phase), prepares to divide (gap 2 or G2-phase), and divides (mitosis or M-phase).
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of...
Two states at the origin of replication
In eukaryotes, the initiation of replication occurs at many sites on the chromosomes, called the origins of...
4.7K