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首页> 外文学位 >Small molecule inhibition of activated MAP kinase signaling in human cancers: Biological and therapeutic implications.
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Small molecule inhibition of activated MAP kinase signaling in human cancers: Biological and therapeutic implications.

机译：在人类癌症中激活MAP激酶信号转导的小分子抑制：生物学和治疗意义。

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摘要

The MAP kinase signaling module (RAS-RAF-MEK-ERK) is a central regulator of cell proliferation, frequently deregulated in human cancers by activating mutations. Proliferation of tumors with mutant BRAF and some with mutant RAS is ERK-dependent and is suppressed by MEK inhibitors. In contrast, tumor cells with receptor tyrosine kinase activation proliferate in a MEK-independent manner. These findings have led to the development of RAF and MEK inhibitors as anticancer agents. Like MEK inhibitors, selective ATP-competitive RAF inhibitors, such as PLX4032, inhibit the proliferation of BRAFV600E tumor cells, but not that of HER kinase-dependent tumors. However, tumors with RAS mutation that are sensitive to MEK inhibition are insensitive to RAF inhibitors. Whereas MEK inhibitors inhibit ERK phosphorylation in all cell types, RAF inhibitors only inhibit ERK signaling in tumor cells expressing BRAF V600E, and paradoxically activate ERK signaling in cells with wild-type RAF. Mutant BRAF-selective responses to RAF inhibitors are also seen at the level of ERK-dependent gene expression. MEK and RAF inhibitors downregulate the transcription of a common set of genes in BRAFV600E tumors cells, while RAF inhibitors transiently induce expression of these genes in tumor cells with wild-type RAF. The mechanism of paradoxical RAF activation has recently been elucidated. In wild-type RAF cells, activation of Ras causes hetero- and homodimerization of RAF molecules, resulting in their activation, and the binding of RAF inhibitors to one protomer in these dimers allosterically trans-activates the other and stimulates downstream effectors. Tumors that express BRAFV600E have low basal levels of active RAS and therefore, low amounts of RAF dimers. Furthermore, because BRAF V600E signals as RAS-independent monomer, RAF inhibitor binding causes direct kinase inhibition and thus suppression of the pathway. These data explain why RAF inhibitors like PLX4032 selectively inhibit the growth of mutant BRAF tumors and suggest that they will not cause toxicity due to the inhibition of ERK signaling in normal cells. This also implies RAF inhibitors enjoy a broader therapeutic index compared to MEK inhibitors.;Recent clinical trials have borne out this prediction, showing that PLX4032 causes tumor regression in most patients with metastatic melanoma with mutant BRAF. Unfortunately these responses are rarely complete, with a median progression of seven months. Meanwhile, the development of low-grade squamous cell carcinoma in the skin of a third of patients may be a side effect related to the drug-mediated induction of ERK signaling in normal tissue. Several drug resistance mechanisms have been elucidated already, and include activating Ras and MEK mutations and upregulated RTK expression. We find that prolonged treatment of BRAF mutant cells with PLX4032 is associated with a rebound of ERK phosphorylation from its nadir. This rebound is accompanied by increases in the transcriptional output of the pathway and could therefore limit the therapeutic effects of the drug. In this new steady state, ERK phosphorylation and output are sensitive to MEK inhibitors but not re-addition of RAF inhibitors. The rebound of ERK signaling is associated with upstream activation in the RAS pathway. We therefore determined the effects of combined RAF and MEK kinase inhibition in a panel of melanoma cells with mutant BRAF. Combined inhibition delayed pathway rebound and resulted in more prolonged suppression of ERK output, enhanced cell death, and tumor growth inhibition compared to treatment with the RAF inhibitor alone. These results suggest that combined RAF and MEK kinase inhibition may be a useful strategy to improve the extent and duration of responses to RAF inhibitors and minimize toxicity caused by ERK activation in normal tissue.
机译：MAP激酶信号传导模块（RAS-RAF-MEK-ERK）是细胞增殖的中央调节剂，在人类癌症中经常通过激活突变使其失控。带有突变BRAF的肿瘤和一些带有突变RAS的肿瘤的增殖是ERK依赖性的，并被MEK抑制剂抑制。相反，具有受体酪氨酸激酶激活的肿瘤细胞以不依赖于MEK的方式增殖。这些发现导致了RAF和MEK抑制剂作为抗癌剂的发展。与MEK抑制剂一样，选择性ATP竞争性RAF抑制剂（例如PLX4032）可抑制BRAFV600E肿瘤细胞的增殖，但不能抑制HER激酶依赖性肿瘤的增殖。但是，对MEK抑制敏感的具有RAS突变的肿瘤对RAF抑制剂不敏感。 MEK抑制剂可在所有细胞类型中抑制ERK磷酸化，而RAF抑制剂仅抑制表达BRAF V600E的肿瘤细胞中的ERK信号传导，并反常激活具有野生型RAF的细胞中的ERK信号传导。在ERK依赖性基因表达水平也可以看到对RAF抑制剂的突变型BRAF选择性反应。 MEK和RAF抑制剂可下调BRAFV600E肿瘤细胞中一组通用基因的转录，而RAF抑制剂可通过野生型RAF瞬时诱导这些基因在肿瘤细胞中的表达。最近阐明了矛盾的RAF激活的机制。在野生型RAF细胞中，Ras的激活会引起RAF分子异二聚和均二聚化，从而导致它们的激活，并且RAF抑制剂与这些二聚体中一个启动子的结合会变构激活另一个，并刺激下游效应子。表达BRAFV600E的肿瘤的基础活性RAS水平较低，因此RAF二聚体含量较低。此外，因为BRAF V600E信号是与RAS无关的单体，所以RAF抑制剂的结合会导致直接的激酶抑制，从而抑制该途径。这些数据解释了为什么RAF抑制剂（如PLX4032）选择性抑制突变型BRAF肿瘤的生长，并表明它们不会由于抑制正常细胞中ERK信号传导而引起毒性。这也意味着RAF抑制剂比MEK抑制剂具有更广泛的治疗指数。近期临床试验证实了这一预测，表明PLX4032在大多数突变型BRAF转移性黑素瘤患者中引起肿瘤消退。不幸的是，这些反应很少完成，平均进展为七个月。同时，三分之一患者皮肤中低级别鳞状细胞癌的发展可能是与药物介导的正常组织ERK信号传导相关的副作用。已经阐明了几种耐药机制，包括激活Ras和MEK突变以及上调RTK表达。我们发现，用PLX4032长时间治疗BRAF突变细胞与ERK磷酸化的最低点有关。这种反弹伴随着该途径的转录输出的增加，因此可能限制药物的治疗效果。在这种新的稳定状态下，ERK的磷酸化和输出对MEK抑制剂敏感，但对RAF抑制剂不敏感。 ERK信号的反弹与RAS通路中的上游激活有关。因此，我们确定了联合的RAF和MEK激酶抑制作用在一组带有突变型BRAF的黑色素瘤细胞中的作用。与单独使用RAF抑制剂治疗相比，联合抑制可延迟途径反弹，并导致对ERK输出的抑制时间更长，细胞死亡增加和肿瘤生长抑制。这些结果表明，联合RAF和MEK激酶抑制可能是一种有用的策略，可改善对RAF抑制剂的反应程度和持续时间，并使正常组织中由ERK激活引起的毒性降至最低。

著录项

  • 作者

    Joseph, Eric.;

  • 作者单位

    Weill Medical College of Cornell University.;

  • 授予单位 Weill Medical College of Cornell University.;
  • 学科 Biology Cell.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 140 p.
  • 总页数 140
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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