响应和抵抗MEK抑制在白血病中,由过度活跃的Ras启动
Jennifer O Lauchle1, Doris Kim, Doan T Le
1Department of Pediatrics, University of California, San Francisco, California 94143, USA.
Nature
|September 4, 2009
概括
MEK 抑制剂在 Nf1 缺乏的急性髓性白血病 (AML) 中表现有前途,但在骨髓增殖性疾病 (MPD) 中表现不佳. 抵抗机制涉及特定的基因突变,为向癌症治疗提供了洞察力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症遗传学 癌症遗传学
背景情况:
- 拉夫/MEK/ERK通路是Ras通路失调的癌症的关键标,包括那些Nf1失活的癌症.
- Nf1编码神经纤维素,GTPase激活蛋白质,可以负面调节Ras信号传输.
- 针对MEK为Nf1缺乏癌症提供了一个潜在的治疗策略.
研究的目的:
- 评估MEK抑制剂在Nf1缺乏的骨髓增殖性疾病 (MPD) 和急性骨髓性白血病 (AML) 的疗效.
- 确定这些癌症中对MEK抑制剂的新生和获得耐药性的机制.
- 探索克服Nf1突变癌症药物耐药性的策略.
主要方法:
- 在Nf1缺乏MPD和AML的小鼠模型中比较MEK抑制剂效应.
- 在AML中使用逆转录病毒插入性突变发生因子诱导合作突变.
- 克隆逆转录病毒整合以确定抗性基因,并对已识别的途径进行功能分析.
主要成果:
- 在Nf1缺乏的MPD中,MEK抑制剂无效.
- MEK 抑制剂在很大比例的 Nf1 缺乏 AML 中诱导了客观回归.
- 药物耐药性源于先前存在的AML克隆,具有已识别的耐药性基因,包括Rasgrp1,Rasgrp4和Mapk14 (p38alpha).
- 增加的RasGRP1水平和减少的p38激酶活性与耐药性有关.
结论:
- MEK 抑制剂在 Nf1 缺乏的血液性恶性瘤中显示出差异性疗效.
- 了解抗性机制,例如涉及RasGRP1和p38alpha的抗性机制,对于开发有效的治疗策略至关重要.
- 这项研究为识别影响针对性疗法的反应和原发性癌细胞抗性的基因和途径提供了一个框架.
相关概念视频
02:38Mitogens and the Cell Cycle
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...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
03:03mTOR Signaling and Cancer Progression
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...
02:56Treatment Resistant Cancers
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...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
01:07MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...