Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back
Resistance of Philadelphia-chromosome positive leukemia towards the kinase inhibitor imatinib (STI571, Glivec): a targeted oncoprotein strikes back
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DOI：
10.1038/sj.leu.2402889
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发表时间：
2003-05
期刊：
影响因子：
11.4
通讯作者：
N. Bubnoff;C. Peschel;J. Duyster
中科院分区：
文献类型：
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作者：
N. Bubnoff;C. Peschel;J. Duyster
过去几十年的癌症研究阐明了信号传导途径，并鉴定了导致或促成细胞恶性转化的基因和蛋白质。 Bcr-Abl 癌蛋白作为导致慢性粒细胞白血病 (CML) 的分子异常的发现，为靶向抗癌疗法的开发铺平了道路。甲磺酸伊马替尼（STI571，格列卫）在 CML 和费城（Ph）染色体阳性急性淋巴细胞白血病（Ph+ ALL）中的显着活性改变了 Ph+ 白血病的治疗方法，并敲响了抗癌治疗新时代的钟声。然而，当继续伊马替尼治疗却出现复发现象时，我们必须吸取伊马替尼可以选择耐药疾病克隆的教训。如果这样的克隆仍然依赖于 Bcr-Abl，它要么携带 BCR-ABL 点突变，阻止药物结合，要么高水平表达融合蛋白。或者，选择具有继发性遗传改变导致不依赖于 Bcr-Abl 增殖的白血病细胞，因为它们在伊马替尼存在下具有生长优势。 BCR-ABL 激酶结构域中的点突变可阻止伊马替尼的结合，但仍允许与 ATP 结合，从而保留 Bcr-Abl 激酶活性。突变的 BCR-ABL 在伊马替尼耐药 Ph+ 白血病病例中经常被检测到，因此代表了研究替代策略以克服耐药性或防止耐药性白血病克隆出现的主要挑战。
Cancer research within the last decades elucidated signaling pathways and identified genes and proteins that lead or contribute to malignant transformation of a cell. Discovery of the Bcr–Abl oncoprotein as the molecular abnormality causing chronic myeloid leukemia (CML) paved the way for the development of a targeted anticancer therapy. The substantial activity of imatinib mesylate (STI571, Glivec) in CML and Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemia (Ph+ ALL) changed the therapeutic approach to Ph+ leukemia and rang the bell for a new era of anticancer treatment. However, when the phenomenon of relapse occurred despite continued imatinib treatment, we had to learn the lesson that imatinib can select for a resistant disease clone. If such a clone still depends on Bcr–Abl, it either carries a BCR–ABL point mutation that prevents binding of the drug or expresses the fusion protein at high levels. Alternatively, leukemia cells that harbor secondary genetic alterations resulting in Bcr–Abl-independent proliferation are selected for their growth advantage in the presence of imatinib. Point mutations in the BCR–ABL kinase domain prevent binding of imatinib but still allow binding of ATP, thus retaining Bcr–Abl kinase activity. Mutated BCR–ABL is frequently detected in cases of imatinib-resistant Ph+ leukemia and therefore represents the main challenge for the investigation of alternative strategies to either overcome resistance or to prevent the emergence of a resistant leukemic clone.