双重向CDK6和LSD1具有协同作用,可以克服AML中的差异化阻塞
Lise Brault1,2, Edwige Voisset1,2, Mathieu Desaunay1,2
1Aix Marseille University, INSERM, CNRS, Institut Paoli-Calmettes, CRCM-Cancer Research Center of Marseille, Marseille, France.
EMBO molecular medicine
|August 29, 2025
概括
结合CDK6和LSD1抑制剂通过恢复骨髓分化和消耗白血病原体来向各种急性髓性白血病 (AML) 细胞. 这种新疗法对临床应用有希望.
科学领域:
- 血液学
- 癌症学
- 分子生物学
背景情况:
- 在急性髓性白血病 (AML) 中,白血病细胞异质性驱动治疗耐药性.
- 针对不同白血病克隆的共同生物过程对于有效的AML治疗至关重要.
- 抑制CDK6在AML细胞中具有脆弱性,可以用于治疗.
研究的目的:
- 确定针对常见的AML细胞脆弱性的组合疗法.
- 研究用于AML治疗的CDK6和LSD1的联合抑制.
- 评估CDK6和LSD1联合抑制在AML中的疗效和作用机制.
主要方法:
- 在AML细胞中利用CDK6的脆弱性.
- 联合抑制循环依赖性激酶6 (CDK6) 和氨酸特异性脱甲酶1 (LSD1).
- 在患者衍生的异种移植 (PDX) 鼠标模型中,评估骨髓细胞分化,白血病原体枯竭,染色质可访问性,基因转录和疗效.
主要成果:
- 结合的CDK6和LSD1抑制恢复骨髓分化并减少AML样本中的白血病原体.
- 这种组合诱导了显著的染色质可访问性变化,促进了分化基因转录和减少了白血病干细胞 (LSC) 签名.
- 在临床前的PDX模型中观察到协同效应,持久的细胞变化和疗效.
- 在仅对LSD1抑制呈现适度反应的AML样本中,共同向CDK6恢复了对LSD1抑制的转录反应.
结论:
- 联合抑制CDK6和LSD1代表了急性髓性白血病的一个有前途的治疗策略.
- 这种组合针对常见的生物途径,克服与白血病异质性相关的抵抗.
- 临床级抑制剂的可用性支持潜在的药物重新定位和临床实施.
相关概念视频
02:57Targeted Cancer Therapies
7.8K
The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
There are several types of targeted therapies against...
7.8K
02:50Combination Therapies and Personalized Medicine
5.1K
Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
5.1K
02:34Inhibition of Cdk Activity
4.9K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.9K
02:15M-Cdk Drives Transition Into Mitosis
5.7K
Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.7K
02:40Cancer Stem Cells and Tumor Maintenance
5.0K
Early diagnosis and treatment can often cure cancer. However, even with treatment, residual cells called cancer stem cells (CSC) might remain, often causing tumor recurrence. These cancer stem cells possess the potential for self-renewal and multi-lineage differentiation and are often responsible for the therapeutic resistance displayed in most cancers.
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
5.0K
02:56Treatment Resistant Cancers
3.4K
Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K