Open AccessEffects of the multi‐kinase inhibitor midostaurin in combination with chemotherapy in models of acute myeloid leukaemia
Author(s) -
Weisberg Ellen,
Meng Chengcheng,
Case Abigail E.,
Tiv Hong L.,
Gokhale Prafulla C.,
Buhrlage Sara J.,
Yang Jing,
Liu Xiaoxi,
Wang Jinhua,
Gray Nathanael,
Adamia Sophia,
Sattler Martin,
Stone Richard,
Griffin James D.
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14927
Subject(s) - midostaurin , medicine , sorafenib , cancer research , myeloid leukemia , pharmacology , fms like tyrosine kinase 3 , oncology , biology , mutation , biochemistry , hepatocellular carcinoma , gene
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.