OHSU Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, LBRB 513, Portland, OR 97239, USA; Howard Hughes Medical Institute, Portland, OR 97239, USA; Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR 97239, USA.
Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Room 4280, Salt Lake City, UT 84112, USA.
Cancer Cell. 2019 Oct 14;36(4):431-443.e5. doi: 10.1016/j.ccell.2019.08.004. Epub 2019 Sep 19.
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-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.
BCR-ABL1 点突变介导的对费城染色体阳性 (Ph) 白血病的酪氨酸激酶抑制剂 (TKI) 治疗的耐药性可以通过几种已批准的药物有效管理，包括 ponatinib 用于 BCR-ABL1 突变疾病。然而，对于携带多个 BCR-ABL1 突变的白血病克隆的患者，治疗选择有限。Asciminib 是一种针对 BCR-ABL1 的豆蔻酰结合口袋的变构抑制剂，对大多数单突变体有效，但对所有测试的复合突变体无效。我们证明，asciminib 与 ATP 结合位点 TKI 联合使用可增强对 Ph 临床分离株和细胞系中靶抑制和耐药性生长的抑制作用。包含 asciminib 可恢复 ponatinib 对目前无法治疗的复合突变体的有效性，达到临床可实现的浓度。我们的研究结果支持将 asciminib 与 ponatinib 联合作为这组分子定义的患者的治疗策略。
