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Leuk Res. 2019 Mar;78:36-44. doi: 10.1016/j.leukres.2018.12.013. Epub 2018 Dec 28.

A kinase profile-adapted drug combination elicits synergistic cooperative effects on leukemic cells carrying BCR-ABL1T315I in Ph+ CML.

Author information

1
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria.
2
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria.
3
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria.
4
Children's Cancer Research Institute (CCRI), Vienna, Austria.
5
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria; Department of Radiation Therapy, Medical University of Vienna, Austria.
6
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria; Department/Clinic for Companion Animals and Horses, Clinic for Small Animals, Clinical Unit of Internal Medicine, University of Veterinary Medicine Vienna, Austria.
7
Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria; Children's Cancer Research Institute (CCRI), Vienna, Austria; Department of Pediatrics, Medical University of Vienna, Austria.
8
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria. Electronic address: peter.valent@meduniwien.ac.at.

Abstract

In chronic myeloid leukemia (CML), resistance against second-generation tyrosine kinase inhibitors (TKI) remains a serious clinical challenge, especially in the context of multi-resistant BCR-ABL1 mutants, such as T315I. Treatment with ponatinib may suppress most of these mutants, including T315I, but is also associated with a high risk of clinically relevant side effects. We screened for alternative treatment options employing available tyrosine kinase inhibitors (TKI) in combination. Dasatinib and bosutinib are two second-generation TKI that bind to different, albeit partially overlapping, spectra of kinase targets in CML cells. This observation prompted us to explore anti-leukemic effects of the combination dasatinib + bosutinib in highly resistant primary CML cells, various CML cell lines (K562, K562R, KU812, KCL22) and Ba/F3 cells harboring various BCR-ABL1 mutant-forms. We found that bosutinib synergizes with dasatinib in inducing growth inhibition and apoptosis in all CML cell lines and in Ba/F3 cells exhibiting BCR-ABL1T315I. Clear synergistic effects were also observed in primary CML cells in all patients tested (n = 20), including drug-resistant cells carrying BCR-ABL1T315I. Moreover, the drug combination produced cooperative or even synergistic apoptosis-inducing effects on CD34+/CD38- CML stem cells. Finally, we found that the drug combination is a potent approach to block the activity of major additional CML targets, including LYN, KIT and PDGFRα. Together, bosutinib and dasatinib synergize in producing anti-leukemic effects in drug-resistant CML cells. Whether such cooperative TKI effects also occur in vivo in patients with drug-resistant CML, remains to be determined in forthcoming studies.

KEYWORDS:

BCR-ABL1 T315I; Bosutinib; Drug combinations; Drug resistance

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