2. Academic Validation
  3. Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells

Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells

  • Cell Death Dis. 2021 Sep 25;12(10):875. doi: 10.1038/s41419-021-04154-0.
Alena Malyukova  # 1,  Dorina Ujvari  # 2,  Elham Yektaei-Karin  # 1,  Ana Zovko  # 1,  Harsha S Madapura 3,  Marton Keszei 3,  Noemi Nagy 4,  Kourosh Lotfi 5 6,  Niclas Björn 6,  Jonas Wallvik 7,  Minori Tamai 8,  Thao T T Nguyen 8,  Koshi Akahane 8,  Takeshi Inukai 8,  Leif Stenke 1 9,  Daniel Salamon 10
Affiliations

Affiliations

  • 1 Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden.
  • 2 Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
  • 3 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
  • 4 Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
  • 5 Department of Hematology, Linköping University Hospital, Linköping, Sweden.
  • 6 Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • 7 Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
  • 8 Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan.
  • 9 Division of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden.
  • 10 Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden. daniel.salamon@ki.se.
  • # Contributed equally.
PMID: 34564697 DOI: 10.1038/s41419-021-04154-0
Abstract

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.

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