Kim Bo-Reum, Jung Seung-Hyun, Han A-Reum, Park Gyeongsin, Kim Hee-Je, Yuan Bin, Battula Venkata Lokesh, Andreeff Michael, Konopleva Marina, Chung Yeun-Jun, Cho Byung-Sik
Leukemia Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
Cancers (Basel). 2020 Jun 30;12(7):1737. doi: 10.3390/cancers12071737.
Given the proven importance of the CXCL12/CXCR4 axis in the stroma-acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-b signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-b in stromal cells or TGF-b-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-b signaling.
鉴于CXCL12/CXCR4轴在基质与急性髓系白血病（AML）相互作用中已被证实的重要性以及对FLT3抑制剂耐药性的迅速出现，我们研究了新型CXCR4抑制剂LY2510924与FLT3抑制剂联合使用在携带FLT3内部串联重复突变（FLT3-ITD）的AML（FLT3-ITD-AML）临床前模型中的疗效和安全性。喹扎替尼是一种强效FLT3抑制剂，可诱导FLT3-ITD-AML细胞凋亡，而LY2510924可阻断表面CXCR4但不诱导凋亡。LY2510924主要通过丝裂原活化蛋白激酶（MAPK）途径显著逆转基质介导的对喹扎替尼的耐药性。在已建立FLT3-ITD-AML模型的小鼠中，LY2510924诱导白血病细胞持久动员和分化，与喹扎替尼联合使用时产生增强的抗白血病作用，而在免疫健全小鼠的非白血病血细胞上观察到短暂效应。对经喹扎替尼和LY2510924体内治疗后存活的白血病细胞转录组进行测序发现，与转化生长因子-β（TGF-β）信号传导相关的基因可能赋予对该药物组合的耐药性。在FLT3-ITD-AML与基质细胞的共培养实验中，基质细胞中TGF-β基因沉默或TGF-β受体激酶抑制剂均可通过联合治疗增强细胞凋亡。LY2510924破坏FLT3-ITD-AML中的CXCL12/CXCR4轴及其对正常免疫细胞的可忽略不计的影响可安全增强喹扎替尼的效力，通过阻断TGF-β信号传导可能会进一步改善疗效。
