对CDK4/6和BRD4的共同向促进了癌症中的衰老和铁死敏感性
Xianbing Zhu1,2, Zheng Fu1,2, Kendall Dutchak3
1Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Cancer research
|January 26, 2024
概括
结合CDK4/6和BRD4抑制剂诱导癌细胞衰老,使它们通过GPX4向对铁亡易受伤害. 这一策略提高了癌症治疗效率.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 循环素依赖性激酶4/6 (CDK4/6) 抑制剂已成为乳腺癌的治疗方法,并且在其他癌症中表现有希望,如KRAS突变非小细胞肺癌 (NSCLC).
- CDK4/6抑制剂的临床使用往往受药物耐药性和主要细胞静止作用的限制,需要新的治疗策略.
研究的目的:
- 确定对CDK4/6抑制剂耐药性的机制,并探索结合疗法来克服这些局限性.
- 为了研究含多马因的蛋白4 (BRD4) 在CDK4/6抑制剂耐药性的作用及其作为治疗点的潜力.
主要方法:
- 全基因组cDNA查,以确定KRAS突变NSCLC细胞中对palbociclib的耐药性因素.
- 使用RNA干扰和小分子抑制剂与palbociclib.lib.结合使用BRD4的抑制.
- 评估细胞衰老,反应性氧物种 (ROS) 积累,GPX4表达和铁亡诱导.
- 在KRAS突变NSCLC小鼠模型和其他癌症细胞系 (胰腺,乳腺) 中评估治疗疗效.
主要成果:
- 确定BRD4过度表达是KRAS突变NSCLC中对palbociclib产生耐药性的机制.
- 在临床前NSCLC模型中,CDK4/6和BRD4的联合抑制协同诱导衰老和延长生存时间.
- 通过调节GPX4水平,BRD4抑制增强了细胞循环停止,ROS积累,并增加了对铁亡的脆弱性.
- 这种组合策略在胰腺和乳腺癌细胞中表现出有效性,这表明其适用性更广泛.
结论:
- 同时准CDK4/6和BRD4是一种有前途的策略,可以克服耐药性并提高CDK4/6抑制剂的疗效.
- 这种组合诱导易受铁灭的衰老癌细胞,提供了一种新的治疗方法.
- 向GPX4与CDK4/6和BRD4抑制剂结合使用可以导致瘤回归和改善生存结果.
相关概念视频
02:34Inhibition of Cdk Activity
4.8K
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...
4.8K
02:15M-Cdk Drives Transition Into Mitosis
5.6K
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...
5.6K
02:57Targeted Cancer Therapies
7.6K
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...
7.6K
01:20The Retinoblastoma Gene
4.1K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.1K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:46Electron Transport Chain: Complex I and II
13.4K
The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
ROS generation is regulated and maintained at moderate levels necessary...
13.4K