2. Academic Validation
  3. Osimertinib covalently binds to CD34 and eliminates myeloid leukemia stem/progenitor cells

Osimertinib covalently binds to CD34 and eliminates myeloid leukemia stem/progenitor cells

  • Cancer Res. 2023 Dec 14. doi: 10.1158/0008-5472.CAN-23-1632.
Li Xia 1,  Jie-Yang Liu 2,  Meng-Ying Yang 2,  Xue-Hong Zhang 3,  Yue Jiang 4,  Qian-Qian Yin 5,  Chen-Hui Luo 6,  Hong-Chen Liu 7,  Zhi-Jie Kang 8,  Cheng-Tao Zhang 7,  Bei-Bei Gao 8,  Ai-Wu Zhou 9,  Hai-Yan Cai 9,  Edmund K Waller 10,  Jin-Song Yan 11,  Ying Lu 2
Affiliations

Affiliations

  • 1 Institute of Dermatology, Xinhua Hospital, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai, China.
  • 2 Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 3 Dalian Medical University, Dalian, Liaoning, China.
  • 4 Dalian Key Laboratory of Hematology, Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, the Second Hospital of Dalian Medical University, Dalian, China, Dalian, China.
  • 5 ShanghaiTech University, Shanghai, China.
  • 6 Shanghai Jiao Tong University, Shanghai, China.
  • 7 Department of Hematology, Liaoning Medical Center for Hematopoietic Stem-Cell Transplantation, Liaoning Key Laboratory of Hematopoietic Stem-Cell Transplantation and Translational Medicine, Dalian Key Laboratory of Hematology, the Second Hospital of Dalian Medical University, Dalian, Liaoning, China.
  • 8 Liaoning Medical Center for Hematopoietic Stem Cell Transplantation, Second Hospital of Dalian Medical University, Dalian, China, Dalian, Liaoning, China.
  • 9 Basic Medical Institute, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, China.
  • 10 Emory University, Atlanta, GA, United States.
  • 11 Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
PMID: 38095536 DOI: 10.1158/0008-5472.CAN-23-1632
Abstract

Osimertinib is a third-generation covalent epidermal growth factor receptor (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 acute myeloid leukemia (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 to their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of AML patients 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 CD34high AML patients 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.

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