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Cited by 5Acute Myeloid Leukemia ResearchChronic Myeloid Leukemia TreatmentsLung Cancer Treatments and Mutations

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

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Xia, Li, Liu, Jie-Yang, Yang, Meng-Ying, Zhang, Xue-Hong, Jiang, Yue, Yin, Qian-Qian, Luo, Chen-Hui, Liu, Hong-Chen, Kang, Zhi-Jie, Zhang, Cheng-Tao, Gao, Bei-Bei, Zhou, Ai-Wu, Cai, Hai-Yan, Waller, Edmund K., Yan, Jin-Song, Lu, Ying·2024·Cancer Research
DOI 10.1158/0008-5472.can-23-1632PMC PMC10831336

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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. Significance: 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.

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Metadata

Authors
Xia, L., Liu, J.-Y., Yang, M.-Y., Zhang, X.-H., Jiang, Y., Yin, Q.-Q., Luo, C.-H., Liu, H.-C., Kang, Z.-J., Zhang, C.-T., Gao, B.-B., Zhou, A.-W., Cai, H.-Y., Waller, E. K., Yan, J.-S., & Lu, Y.
Affiliations
  • 1Institute of Dermatology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • Shanghai Jiao Tong University (CN)
  • 3Center of Genome and Personalized Medicine, Institute of Cancer Stem Cell, Dalian Medical University, Liaoning, China.
  • Dalian Medical University (CN)
  • 5Shanghai Institute for Advanced Immunochemical Studies, Shanghai Tech University, Shanghai, China.
  • 4Department 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, China.
  • 6Basic Medical Institute, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Winship Cancer Institute (US)
Corresponding author
Lu, Ying
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2023-12-14
Volume
84
Issue
3
Pages
479-492
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-23-1632
PMC
PMC10831336
OpenAlex
W4389732350
Cited by
5
References
4
Citations by year
2025: 3 · 2024: 2
FWCI
1.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (82170179, 81970131, 81370652, 81770146, 32171431)
  • Science and Technology Commission of Shanghai Municipality (22S11900400)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
osimertinib, CD34, acute myeloid leukemia, chronic myeloid leukemia, covalent binding, apoptosis, Src family kinases, STAT3 signaling, synthetic lethality, prognostic factors, patient-derived xenografts, compassionate use
MeSH terms
Acrylamides, Aniline Compounds, Carcinoma, Non-Small-Cell Lung, Humans, Indoles, Lung Neoplasms, Pyrimidines, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Antigens, CD34, Myeloid Progenitor Cells, Proteomics, Cell Proliferation, ErbB Receptors

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