Effects of the multi-kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia.

Autor: Weisberg E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Meng C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Case AE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Tiv HL; Experimental Therapeutic Core, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Gokhale PC; Experimental Therapeutic Core, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Buhrlage SJ; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Yang J; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Liu X; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Wang J; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Gray N; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Adamia S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Sattler M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Stone R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA., Griffin JD; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: Journal of cellular and molecular medicine [J Cell Mol Med] 2020 Mar; Vol. 24 (5), pp. 2968-2980. Date of Electronic Publication: 2020 Jan 22.
DOI: 10.1111/jcmm.14927
Abstrakt: Recently, several targeted agents have been developed for specific subsets of patients with acute myeloid leukaemia (AML), including midostaurin, the first FDA-approved FLT3 inhibitor for newly diagnosed patients with FLT3 mutations. However, in the initial Phase I/II clinical trials, some patients without FLT3 mutations had transient responses to midostaurin, suggesting that this multi-targeted kinase inhibitor might benefit AML patients more broadly. Here, we demonstrate submicromolar efficacy of midostaurin in vitro and efficacy in vivo against wild-type (wt) FLT3-expressing AML cell lines and primary cells, and we compare its effectiveness with that of other FLT3 inhibitors currently in clinical trials. Midostaurin was found to synergize with standard chemotherapeutic drugs and some targeted agents against AML cells without mutations in FLT3. The mechanism may involve, in part, the unique kinase profile of midostaurin that includes proteins implicated in AML transformation, such as SYK or KIT, or inhibition of ERK pathway or proviability signalling. Our findings support further investigation of midostaurin as a chemosensitizing agent in AML patients without FLT3 mutations.
(© 2020 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
Databáze: MEDLINE
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