Activation of tropomyosin receptor kinase (TRK) family tyrosine kinases by chromosomal rearrangement has been shown to drive a wide range of solid tumors and hematologic malignancies. TRK fusions are actionable targets as evidenced by recent clinical trial results in solid tumors. Entrectinib (RXDX-101) is an investigational, orally available, CNS-active, highly potent, and selective kinase inhibitor against TRKA/B/C, ROS1, and ALK kinase activities. Here, we demonstrate that TRK kinase inhibition by entrectinib selectively targets preclinical models of TRK fusion–driven hematologic malignancies. In acute myelogenous leukemia (AML) cell lines with endogenous expression of the ETV6–NTRK3 fusion gene, entrectinib treatment blocked cell proliferation and induced apoptotic cell death in vitro with subnanomolar IC50 values. Phosphorylation of the ETV6–TRKC fusion protein and its downstream signaling effectors was inhibited by entrectinib treatment in a dose-dependent manner. In animal models, entrectinib treatment at clinically relevant doses resulted in tumor regression that was accompanied by elimination of residual cancer cells from the bone marrow. Our preclinical data demonstrate the potential of entrectinib as an effective treatment for patients with TRK fusion–driven AML and other hematologic malignancies. Mol Cancer Ther; 17(2); 455–63. ©2017 AACR.

中文翻译：

---

Entrectinib（一种 Pan-TRK、ROS1 和 ALK 抑制剂）在 ETV6-NTRK3 阳性急性髓系白血病中的抗肿瘤活性

通过染色体重排激活原肌球蛋白受体激酶 (TRK) 家族酪氨酸激酶已被证明可驱动多种实体瘤和血液系统恶性肿瘤。最近在实体瘤中的临床试验结果证明，TRK 融合是可行的目标。Entrectinib (RXDX-101) 是一种研究性、可口服、具有 CNS 活性、高效、选择性的激酶抑制剂，可抑制 TRKA/B/C、ROS1 和 ALK 激酶活性。在这里，我们证明了 entrectinib 对 TRK 激酶的抑制选择性地靶向 TRK 融合驱动的血液系统恶性肿瘤的临床前模型。在具有 ETV6-NTRK3 融合基因内源性表达的急性髓性白血病 (AML) 细胞系中，entrectinib 治疗在体外阻断细胞增殖并诱导凋亡细胞死亡，IC50 值为亚纳摩尔。ETV6-TRKC 融合蛋白及其下游信号传导效应子的磷酸化被 entrectinib 治疗以剂量依赖性方式抑制。在动物模型中，临床相关剂量的 entrectinib 治疗导致肿瘤消退，同时消除骨髓中残留的癌细胞。我们的临床前数据证明了 entrectinib 作为 TRK 融合驱动的 AML 和其他血液系统恶性肿瘤患者的有效治疗方法的潜力。摩尔癌症治疗; 17(2); 455-63。©2017 AACR。我们的临床前数据证明了 entrectinib 作为 TRK 融合驱动的 AML 和其他血液系统恶性肿瘤患者的有效治疗方法的潜力。摩尔癌症治疗; 17(2); 455-63。©2017 AACR。我们的临床前数据证明了 entrectinib 作为 TRK 融合驱动的 AML 和其他血液系统恶性肿瘤患者的有效治疗方法的潜力。摩尔癌症治疗; 17(2); 455-63。©2017 AACR。