Universitätsklinikum Jena, Jena, Germany.
Cell Cycle. 2011 Jan 15;10(2):250-60. doi: 10.4161/cc.10.2.14537.
Therapies that target BCR-ABL in chronic myeloid leukemia, including imatinib, dasatinib and nilotinib, have dramatically improved patient outcome. BCR-ABL mutations, however, contribute to treatment resistance by disrupting drug contact sites or causing conformational changes thus making contact sites inaccessible. Clinical data indicate that developing BCR-ABL mutations during imatinib treatment is predictive for shorter progression-free survival, and that outcomes may depend on mutation type or location. In vitro, dasatinib and nilotinib inhibit most imatinib-resistant BCR-ABL mutations, except for T315I. In clinical studies, other mutations associated with treatment resistance include V299L, T315A, and F317I/L for dasatinib and Y253F/H, E255K/V, and F359C/V for nilotinib. Evaluating patients with clinical signs of resistance for BCR-ABL mutations is an important component of disease monitoring, potentially facilitating selection of subsequent therapy. First-line treatment with dasatinib or nilotinib instead of imatinib may reduce emergence of resistance but novel agents are needed to overcome the problematic T315I mutation.
针对慢性髓性白血病中的 BCR-ABL 的治疗方法，包括伊马替尼、达沙替尼和尼洛替尼，极大地改善了患者的预后。然而，BCR-ABL 突变通过破坏药物接触点或引起构象变化，从而使接触点无法接近，导致治疗耐药。临床数据表明，在伊马替尼治疗期间发生 BCR-ABL 突变与无进展生存期较短相关，并且结果可能取决于突变类型或位置。在体外，达沙替尼和尼洛替尼抑制大多数伊马替尼耐药的 BCR-ABL 突变，除了 T315I 突变。在临床研究中，与治疗耐药相关的其他突变包括达沙替尼的 V299L、T315A 和 F317I/L，以及尼洛替尼的 Y253F/H、E255K/V 和 F359C/V。评估有耐药临床迹象的患者是否存在 BCR-ABL 突变是疾病监测的重要组成部分，可能有助于选择后续治疗。一线使用达沙替尼或尼洛替尼而不是伊马替尼可能会减少耐药的出现，但需要新的药物来克服有问题的 T315I 突变。
