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Nature:阿西替尼的抗白血病潜力

摘要 : 在来自 CML 和ALL患者的初生细胞中对已经被批准上市和仍处在研究阶段的抗癌药物所做的这项大规模筛选中,Krister Wennerberg及同事发现 “阿西替尼”(一种被批准用于治疗肾癌的多激酶抑制剂)在来自初发患者的CML和ALL细胞中(包括在具有二次抵抗力突变的细胞中)具有活性。

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很多慢性骨髓性白血病(CMLs)和急性淋巴细胞白血病(ALLs)都是由BCR-ABL融合基因造成的。用选择性激酶抑制剂以BCR-ABL为目标进行治疗使CML白血病的治疗发生了革命性变化,但患者经常会对治疗产生抵抗力,原因经常是由于BCR-ABL发生了二次突变。

在来自 CML 和ALL患者的初生细胞中对已经被批准上市和仍处在研究阶段的抗癌药物所做的这项大规模筛选中,Krister Wennerberg及同事发现 “阿西替尼”(一种被批准用于治疗肾癌的多激酶抑制剂)在来自初发患者的CML和ALL细胞中(包括在具有二次抵抗力突变的细胞中)具有活性。在一位CML患者身上(对这位患者其他所有治疗方案都已用尽),通过“阿西替尼”的诱导,循环的BCR-ABL转录体水平降低了。这些初步的临床发现显示了将现有药物改变用途用于治疗其他类型癌症所具有的潜力。

原文链接:Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation 

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30–50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selecive and effective inhibitor for T315I-mutant BCR–ABL1-driven leukaemia. Axitinib potently inhibited BCR–ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selecive binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

来源: Nature 浏览次数:67

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