Osimertinib Covalently Binds to CD34 and Eliminates Myeloid Leukemia Stem/Progenitor Cells

作者：Xia Li, Jie-Yang Liu, Meng‐Ying Yang, Xuehong Zhang, Yue Jiang, Qianqian Yin, Chen‐Hui Luo, Hong-Chen Liu, Zhijie Kang, Cheng-Tao Zhang, Bei-Bei Gao, Aiwu Zhou, Haiyan Cai, Edmund K. Waller, Jinsong Yan, Ying Lu · 发表于：Cancer Research · 年份：2023 · DOI：10.1158/0008-5472.can-23-1632 · 被引用次数：5 · 研究领域：Chronic Myeloid Leukemia Treatments、Lung Cancer Treatments and Mutations、Acute Myeloid Leukemia Research

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 de...