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Abstract：
Osimertinib is a third-generation covalent EGFR inhibitor that is used in treating non-small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34- cells in EGFR-negative AML and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared with their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of patients with AML with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two patients with CD34high AML who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia.
UNASSIGNED: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
UNASSIGNED: Osimertinib binds CD34 and selectively kills CD34+ leukemia cells to induce remission in preclinical models and patients with AML with a high percentage of CD34+ blasts, providing therapeutic options for myeloid leukemia patients.
摘要：
Osimertinib是第三代共价EGFR抑制剂，用于治疗非小细胞肺癌。在临床前研究中发现第一代EGFR抑制剂对急性髓系白血病（AML）细胞具有诱导分化作用，但临床试验结果大多为阴性.这里,我们报道,在EGFR阴性AML和慢性粒细胞白血病(CML)中,奥希替尼选择性诱导CD34+白血病干/祖细胞凋亡,而非CD34-细胞凋亡.奥希替尼与半胱氨酸199和177处的CD34共价结合以及Src家族激酶(SFK)和下游STAT3活化的抑制有助于奥希替尼诱导的细胞死亡。SFK和STAT3抑制在原代CD34+细胞中使用奥希替尼诱导合成致死性。与正常细胞相比，AML细胞中CD34的表达升高。基因组，转录组，蛋白质组学分析确定了CD34高表达的AML患者的突变和基因表达特征，单因素和多因素分析表明CD34高表达具有不良预后意义。奥希替尼治疗在AML患者来源的异种移植模型中诱导应答,其与CD34表达相关,同时保留正常CD34+细胞。在两名CD34highAML患者中观察到临床反应，他们在同情使用的基础上接受了奥希替尼治疗。这些发现揭示了奥希替尼治疗CD34highAML和CML的治疗潜力，并描述了奥希替尼诱导髓性白血病细胞死亡的EGFR非依赖性机制。
奥希替尼结合CD34并选择性杀死CD34+白血病细胞，从而在临床前模型和CD34+母细胞比例高的AML患者中诱导缓解，为髓系白血病患者提供治疗选择。
奥希替尼结合CD34并选择性杀死CD34+白血病细胞，从而在临床前模型和CD34+母细胞比例高的AML患者中诱导缓解，为髓系白血病患者提供治疗选择。
