Ye Wu, Wu Xia, Wang Xiaojia, Wei Xiaoyu, Tang Yuqian, Ouyang Xianfeng, Gong Yuping
Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Front Pharmacol. 2022 Oct 3;13:931772. doi: 10.3389/fphar.2022.931772. eCollection 2022.
Patients with chronic myeloid leukemia (CML) show resistance to tyrosine kinase inhibitors (TKIs) targeting ABL1 due to the emergence of BCR::ABL1 mutants, especially compound mutants during the treatment, which brings great challenges to clinical practice. Combination therapy is an effective strategy for drug resistance. GMB-475, a proteolysis targeting chimera (PROTAC) targeting the myristoyl pocket of ABL1 in an allosteric manner, degrades the BCR::ABL1 through the ubiquitin-proteasome pathway. In this study, we combined GMB-475 with orthosteric TKIs targeting ABL1 to overcome resistance. We constructed Ba/F3 cells carrying BCR::ABL1 mutants by gene cloning technology and compared the effects of combination therapy with those of monotherapy on the biological characteristics and signaling pathways in CML cells. We found that the effects of ABL1 inhibitors, including imatinib, dasatinib, ponatinib, and ABL001, on growth inhibition and promoting apoptosis of Ba/F3 cells with BCR::ABL1 mutants, especially compound mutants, were weakened. GMB-475 combined with TKIs, especially dasatinib, synergistically inhibited growth, promoted apoptosis, and blocked the cell cycle of Ba/F3 cells carrying BCR::ABL1 mutants and synergistically blocked multiple molecules in the JAK-STAT pathway. In conclusion, dasatinib enhanced the antitumor effect of GMB-475; that is, the combination of PROTAC targeting ABL1 in an allosteric manner and orthosteric TKIs, especially dasatinib, provides a novel idea for the treatment of CML patients with BCR::ABL1 mutants in clinical practice.
慢性髓性白血病（CML）患者由于BCR::ABL1突变体的出现，尤其是在治疗过程中出现的复合突变体，对靶向ABL1的酪氨酸激酶抑制剂（TKIs）产生耐药性，这给临床实践带来了巨大挑战。联合治疗是解决耐药性的有效策略。GMB-475是一种以变构方式靶向ABL1肉豆蔻酰口袋的蛋白酶靶向嵌合体（PROTAC），通过泛素-蛋白酶体途径降解BCR::ABL1。在本研究中，我们将GMB-475与靶向ABL1的正构TKIs联合使用以克服耐药性。我们通过基因克隆技术构建了携带BCR::ABL1突变体的Ba/F3细胞，并比较了联合治疗与单一疗法对CML细胞生物学特性和信号通路的影响。我们发现，伊马替尼、达沙替尼、波纳替尼和ABL001等ABL1抑制剂对携带BCR::ABL1突变体，尤其是复合突变体的Ba/F3细胞的生长抑制和促凋亡作用减弱。GMB-475与TKIs，尤其是达沙替尼联合使用，可协同抑制携带BCR::ABL1突变体的Ba/F3细胞的生长、促进凋亡并阻断细胞周期，还可协同阻断JAK-STAT途径中的多个分子。总之，达沙替尼增强了GMB-475的抗肿瘤作用；也就是说，以变构方式靶向ABL1的PROTAC与正构TKIs，尤其是达沙替尼联合使用，为临床治疗携带BCR::ABL1突变体的CML患者提供了新思路。
