Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants
Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants
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DOI：
10.1016/j.ccell.2019.08.004
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发表时间：
2019-10-14
期刊：
影响因子：
50.3
通讯作者：
Deininger, Michael W.
中科院分区：
文献类型：
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作者：
Eide, Christopher A.;Zabriskie, Matthew S.;Deininger, Michael W.
费城染色体阳性 (Ph+) 白血病中 BCR-ABL1 点突变介导的酪氨酸激酶抑制剂 (TKI) 治疗耐药性可通过多种已获批准的药物得到有效控制，其中包括用于 BCR-ABL1(T3151) 突变性疾病的普纳替尼 (ponatinib)。然而，对于携带多个 BCR-ABL1 突变的白血病克隆患者，治疗选择有限。 Asciminib 是一种针对 BCR-ABL1 肉豆蔻酰结合袋的变构抑制剂，对大多数单一突变体有活性，但对所有测试的复合突变体无效。我们证明，阿西米尼与 ATP 位点 TKI 组合可增强靶标抑制作用，并抑制 Ph+ 临床分离株和细胞系中耐药性的生长。阿西米尼的加入恢复了普纳替尼在临床可达到的浓度下对抗目前无法治疗的化合物突变体的有效性。我们的研究结果支持将阿西米尼与普纳替尼联合作为这一分子定义的患者组的治疗策略。
BCR-ABL1 point mutation-mediated resistance to tyrosine kinase inhibitor (TKI) therapy in Philadelphia chromosome-positive (Ph+) leukemia is effectively managed with several approved drugs, including ponatinib for BCR-ABL1(T3151) -mutant disease. However, therapy options are limited for patients with leukemic clones bearing multiple BCR-ABL1 mutations. Asciminib, an allosteric inhibitor targeting the myristoyl-binding pocket of BCR-ABL1, is active against most single mutants but ineffective against all tested compound mutants. We demonstrate that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines. Inclusion of asciminib restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations. Our findings support combining asciminib with ponatinib as a treatment strategy for this molecularly defined group of patients.