Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, 391 82, Sweden.
BMC Cancer. 2020 May 7;20(1):397. doi: 10.1186/s12885-020-06782-9.
Chronic myeloid leukaemia is in principle a treatable malignancy but drug resistance is lowering survival. Recent drug discoveries have opened up new options for drug combinations, which is a concept used in other areas for preventing drug resistance. Two of these are (I) Axitinib, which inhibits the T315I mutation of BCR-ABL1, a main source of drug resistance, and (II) Asciminib, which has been developed as an allosteric BCR-ABL1 inhibitor, targeting an entirely different binding site, and as such does not compete for binding with other drugs. These drugs offer new treatment options.
We measured the proliferation of KCL-22 cells exposed to imatinib-dasatinib, imatinib-asciminib and dasatinib-asciminib combinations and calculated combination index graphs for each case. Moreover, using the median-effect equation we calculated how much axitinib can reduce the growth advantage of T315I mutant clones in combination with available drugs. In addition, we calculated how much the total drug burden could be reduced by combinations using asciminib and other drugs, and evaluated which mutations such combinations might be sensitive to.
Asciminib had synergistic interactions with imatinib or dasatinib in KCL-22 cells at high degrees of inhibition. Interestingly, some antagonism between asciminib and the other drugs was present at lower degrees on inhibition. Simulations revealed that asciminib may allow for dose reductions, and its complementary resistance profile could reduce the risk of mutation based resistance. Axitinib, however, had only a minor effect on T315I growth advantage.
Given how asciminib combinations were synergistic in vitro, our modelling suggests that drug combinations involving asciminib should allow for lower total drug doses, and may result in a reduced spectrum of observed resistance mutations. On the other hand, a combination involving axitinib was not shown to be useful in countering drug resistance.
慢性髓性白血病原则上是一种可治疗的恶性肿瘤，但耐药性正在降低生存率。最近的药物发现为药物组合开辟了新的选择，这是在其他领域用于预防耐药性的概念。其中两种是（I）阿昔替尼，它抑制 BCR-ABL1 的 T315I 突变，这是耐药性的主要来源，（II）ASCiminib，它被开发为别构 BCR-ABL1 抑制剂，针对完全不同的结合位点，因此不与其他药物竞争结合。这些药物提供了新的治疗选择。
我们测量了暴露于伊马替尼-达沙替尼、伊马替尼-ASCiminib 和达沙替尼-ASCiminib 组合的 KCL-22 细胞的增殖，并为每种情况计算了组合指数图。此外，使用中位数效应方程，我们计算了阿昔替尼可以降低 T315I 突变体克隆与现有药物联合生长优势的程度。此外，我们计算了使用 ASCiminib 和其他药物组合可以减少多少总药物负担，并评估了这些组合可能对哪些突变敏感。
ASCiminib 在 KCL-22 细胞中与伊马替尼或达沙替尼在高度抑制时具有协同相互作用。有趣的是，在较低的抑制程度下，ASCiminib 与其他药物之间存在一些拮抗作用。模拟结果表明，ASCiminib 可能允许减少剂量，其互补的耐药谱可以降低基于突变的耐药风险。然而，阿昔替尼对 T315I 生长优势的影响很小。
鉴于 ASCiminib 组合在体外具有协同作用，我们的模型表明，涉及 ASCiminib 的药物组合应允许降低总药物剂量，并可能导致观察到的耐药突变谱减少。另一方面，涉及阿昔替尼的组合在对抗耐药性方面没有显示出有用性。
