Effects of the Multi-kinase Inhibitor Midostaurin in Combination with Chemotherapy in Models of Acute Myeloid Leukaemia

Overview

Journal J Cell Mol Med

Specialties Cell Biology
Molecular Biology

Date 2020 Jan 23

PMID 31967735

Citations 13

Authors

Ellen Weisberg

Chengcheng Meng

Abigail E Case

Hong L Tiv

Prafulla C Gokhale

Sara J Buhrlage

Jing Yang

Xiaoxi Liu

Jinhua Wang

Nathanael Gray

Sophia Adamia

Martin Sattler

Richard Stone

James D Griffin

Affiliations

Soon will be listed here.

Abstract

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.

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