Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy.
Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy.
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DOI：
10.1186/s12943-018-0780-6
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发表时间：
2018-02-19
期刊：
影响因子：
37.3
通讯作者：
Martinelli G
中科院分区：
文献类型：
--
作者：
Soverini S;Mancini M;Bavaro L;Cavo M;Martinelli G
BCR-ABL 1是一种由t（9;22）（q34;q11）染色体易位引起的融合基因编码的非受体酪氨酸激酶，其活性失调被认为是导致慢性粒细胞白血病（CML）发生和维持的驱动事件。BCR-ABL 1是第一个涉及人类恶性肿瘤的酪氨酸激酶之一，也是第一个成功靶向的酪氨酸激酶。甲磺酸伊马替尼是第一个被批准用于治疗用途的酪氨酸激酶抑制剂（TKI），被誉为对抗癌症的灵丹妙药，并且仍然是有史以来开发的最安全，最有效的抗癌药物之一。后来引入了第二代和第三代TKI，以预防或抵消可能在一小部分患者中出现的耐药性问题。它们是更有效的分子，但与更严重的副作用和并发症有关。预计对TKI治疗达到稳定最佳应答的患者的预期寿命与一般人群相同。然而，TKI不能“治愈”CML。只有一小部分病例可能会尝试停止治疗，而不会出现随后的复发。绝大多数患者将不得不无限期地服用TKI-这引起了严重的药物经济学问题，现在将重点从疗效转移到依从性和生活质量问题。在这里，我们追溯了从BCR-ABL 1结构和功能的生物学收购到抑制策略发展的步骤，并讨论了耐药机制以及如何解决这些问题。本文的在线版本（10.1186/s12943-018-0780-6）包含补充材料，可供授权用户使用。
Deregulated activity of BCR-ABL1, a nonreceptor tyrosine kinase encoded by the fusion gene resulting from the t(9;22)(q34;q11) chromosomal translocation, is thought to be the driver event responsible for initiation and maintenance of chronic myeloid leukemia (CML). BCR-ABL1 was one of the first tyrosine kinases to be implicated in a human malignancy and the first to be successfully targeted. Imatinib mesylate, the first tyrosine kinase inhibitor (TKI) to be approved for therapeutic use, was hailed as a magic bullet against cancer and remains one of the safest and most effective anticancer agents ever developed. Second- and third-generation TKIs were later introduced to prevent or counteract the problem of drug resistance, that may arise in a small proportion of patients. They are more potent molecules, but have been associated to more serious side effects and complications. Patients achieving stable optimal responses to TKI therapy are predicted to have the same life expectancy of the general population. However, TKIs do not ‘cure’ CML. Only a small proportion of cases may attempt therapy discontinuation without experiencing subsequent relapse. The great majority of patients will have to assume TKIs indefinitely – which raises serious pharmacoeconomic concerns and is now shifting the focus from efficacy to compliance and quality of life issues. Here we retrace the steps that have led from the biological acquisitions regarding BCR-ABL1 structure and function to the development of inhibitory strategies and we discuss drug resistance mechanism and how they can be addressed. The online version of this article (10.1186/s12943-018-0780-6) contains supplementary material, which is available to authorized users.
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影响因子：
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