2019年9月19日，美国犹他大学Michael W. Deininger、俄勒冈健康与科学大学Brian J. Druker等研究人员合作在《癌细胞》杂志在线发表论文，发现将变构抑制剂asciminib与ponatinib结合可抑制高抗性BCR-ABL1突变体的出现并恢复其功效。

研究人员介绍，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）治疗抗性能够由几种批准的药物进行有效治疗，包括用于BCR-ABL1T315I突变疾病的ponatinib。然而，对于携带多种BCR-ABL1突变的白血病克隆患者，治疗选择是有限的。asciminib是一种针对BCR-ABL1的肉豆蔻酰结合口袋的变构抑制剂，对大多数单突变体具有活性，但对所有测试的化合物突变体无效。

研究人员证明，将asciminib与ATP位点TKI组合可增强Ph+临床分离株和细胞系中的靶抑制和抑制抗性生长。在临床可达到的浓度下，加入asciminib可恢复ponatinib对目前无法治愈的化合物突变体的有效性。这些研究结果表明将asciminib与ponatinib联合能够作为这一分子定义患者类型的治疗策略。

附：英文原文

Title: Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants

Author: Christopher A. Eide, Matthew S. Zabriskie, Samantha L. Savage Stevens, Orlando Antelope, Nadeem A. Vellore, Hein Than, Anna Reister Schultz, Phillip Clair, Amber D. Bowler, Anthony D. Pomicter, Dongqing Yan, Anna V. Senina, Wang Qiang, Todd W. Kelley, Philippe Szankasi, Michael C. Heinrich, Jeffrey W. Tyner, Delphine Rea, Jean-Michel Cayuela, Dong-Wook Kim, Cristina E. Tognon, Thomas OHare, Brian J. Druker, Michael W. Deininger

Issue&Volume: 19 September 2019

Abstract: 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 ponatinibs 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.

DOI: 10.1016/j.ccell.2019.08.004

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30372-1