BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML
BCR-ABL- and Ras-independent activation of Raf as a novel mechanism of Imatinib resistance in CML
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DOI：
10.3892/ijo.2011.1062
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发表时间：
2011-09-01
影响因子：
5.2
通讯作者：
Von Eggeling, Ferdinand
中科院分区：
文献类型：
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作者：
Hentschel, Julia;Rubio, Ignacio;Von Eggeling, Ferdinand
虽然BCR-ABL酪氨酸激酶抑制剂伊马替尼无疑为慢性粒细胞白血病（CML）的治疗带来了革命性的变化，但获得性耐药仍然是CML治疗中的常见问题。耐药通常来自BCR-ABL的二线突变或BCR-ABL蛋白的过表达，但在类似20%的CML病例中，耐药机制不涉及BCR-ABL功能的改变。伊马替尼耐药CML细胞系已被广泛用于比较蛋白质组/全基因组表达筛选，以破译耐药机制，但这些研究尚未发展出BCR-ABL非依赖性伊马替尼耐药的明确分子机制或分子参与者。在这里，我们报告了BCR-ABL功能未改变的CML细胞中伊马替尼耐药的新机制的鉴定。药理学分析证明了组成性的，伊马替尼不敏感的Erk-MAPK途径的激活在耐药细胞。途径成分的系统分析表明，Ras-GTP积累仍然完全敏感伊马替尼，但c-Raf活性从血清喂养的文化是很大程度上耐药的药物的作用。测序排除了B-Raf或c-Raf中的突变作为抗性的起源，表明c-Raf活性调节中的功能改变是造成这种效应的原因。总的来说，这些研究结果强调了一种新的获得性伊马替尼耐药机制，该机制基于通过活化的c-Raf对Erk-MAPK通路的BCR-ABL和Ras非依赖性组成性活化，这可能有助于对CML中伊马替尼耐药原因进行更好的功能分类。
Although the BCR-ABL tyrosine kinase inhibitor Imatinib has undoubtedly revolutionized the therapy of chronic myeloid leukaemia (CML), acquired drug resistance remains a common problem in CML therapy. Resistance often arises from second-line mutations in BCR-ABL or overexpression of the BCR-ABL protein but in similar to 20% of CML cases resistance mechanisms do not involve altered BCR-ABL function. Imatinib-resistant CML cell lines have been widely used for comparative proteome/genome-wide expression screens in order to decipher resistance mechanisms but a clearcut molecular mechanism or molecular player in BCR-ABL-independent resistance to Imatinib has not yet evolved from those studies. Here, we report the identification of a novel mechanism for Imatinib resistance in CML cells with unaltered BCR-ABL function. Pharmacological analysis evidenced a constitutive, Imatinib-insensitive activation of the Erk-MAPK pathway in resistant cells. A systematic analysis of pathway constituents illustrated that Ras-GTP accumulation remained fully sensitive to Imatinib but c-Raf activity from serum-fed cultures was largely resistant to the drug's action. Sequencing excluded mutations in either B-Raf or c-Raf as the origin of resistance, indicating that a functional alteration in the regulation of c-Raf activity was responsible for this effect. Collectively, these findings highlight a novel mechanism of acquired Imatinib resistance based on the BCR-ABL and Ras-independent constitutive activation of the Erk-MAPK pathway through activated c-Raf, which could prove helpful for a better functional classification of the causes of Imatinib resistance in CML.