Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, Oregon, USA.
Clin Cancer Res. 2011 Jan 15;17(2):212-21. doi: 10.1158/1078-0432.CCR-09-3314. Epub 2010 Nov 22.
Beginning with imatinib a decade ago, therapy based on targeted inhibition of the BCR-ABL kinase has greatly improved the prognosis for chronic myeloid leukemia (CML) patients. The recognition that some patients experience relapse due to resistance-conferring point mutations within BCR-ABL sparked the development of the second-generation ABL kinase inhibitors nilotinib and dasatinib. Collectively, these drugs target most resistant BCR-ABL mutants, with the exception of BCR-ABL(T315I). A third wave of advances is now cresting in the form of ABL kinase inhibitors whose target profile encompasses BCR-ABL(T315I). The leading third-generation clinical candidate for treatment-refractory CML, including patients with the T315I mutation, is ponatinib (AP24534), a pan-BCR-ABL inhibitor that has entered pivotal phase 2 testing. A second inhibitor with activity against the BCR-ABL(T315I) mutant, DCC-2036, is in phase 1 clinical evaluation. We provide an up-to-date synopsis of BCR-ABL signaling pathways, highlight new findings on mechanisms underlying BCR-ABL mutation acquisition and disease progression, discuss the use of nilotinib and dasatinib in a first-line capacity, and evaluate ponatinib, DCC-2036, and other ABL kinase inhibitors with activity against BCR-ABL(T315I) in the development pipeline.
从十年前的伊马替尼开始，基于靶向抑制 BCR-ABL 激酶的治疗极大地改善了慢性髓性白血病（CML）患者的预后。认识到一些患者由于 BCR-ABL 内的耐药性赋予点突变而复发，激发了第二代 ABL 激酶抑制剂尼罗替尼和达沙替尼的开发。这些药物共同针对大多数耐药 BCR-ABL 突变体，除了 BCR-ABL(T315I)。现在，以 ABL 激酶抑制剂为形式的第三波进展正在达到顶峰，这些抑制剂的目标谱包括 BCR-ABL(T315I)。治疗难治性 CML 的第三代临床候选药物，包括具有 T315I 突变的患者，是 ponatinib（AP24534），一种泛 BCR-ABL 抑制剂，已进入关键的 2 期测试。另一种对 BCR-ABL(T315I)突变体具有活性的抑制剂 DCC-2036，正在进行 1 期临床评估。我们提供了对 BCR-ABL 信号通路的最新综述，强调了关于 BCR-ABL 突变获得和疾病进展的机制的新发现，讨论了在一线使用尼罗替尼和达沙替尼的情况，并评估了 ponatinib、DCC-2036 以及其他在开发管道中对 BCR-ABL(T315I)具有活性的 ABL 激酶抑制剂。
