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-ABL1T315I-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.

中文翻译：

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将变构抑制剂Asciminib与Ponatinib联合使用可抑制高耐药BCR-ABL1突变体的出现并恢复其功效。

在费城染色体阳性（Ph +）白血病中，BCR-ABL1点突变介导的对酪氨酸激酶抑制剂（TKI）治疗的耐药性已通过多种批准的药物得到有效管理，其中包括用于BCR-ABL1T315I突变疾病的ponatinib。但是，对于患有携带多个BCR-ABL1突变的白血病克隆的患者，治疗选择受到限制。Asciminib是一种靶向BCR-ABL1的肉豆蔻酰基结合口袋的变构抑制剂，对大多数单个突变体均具有活性，但对所有测试的化合物突变体均无效。我们证明，结合asciminib和ATP位点TKIs可以增强Ph +临床分离株和细胞系中的靶标抑制作用和耐药性增生抑制。在临床上可达到的浓度下，加入asciminib可恢复ponatinib对目前无法治疗的化合物突变体的有效性。