Abstract
FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. Thus, a better understanding of drug-resistance pathways could be a good strategy to explore and evaluate new combinational therapies for AML. Here, we used phosphoproteomics to identify differentially-phosphorylated proteins in patients with AML and TKI resistance. We then studied resistance mechanisms in vitro and evaluated the efficacy and safety of rational combinational therapy in vitro, ex vivo and in vivo in mice. Proteomic and immunohistochemical studies showed the sustained activation of ERK1/2 in bone marrow samples of patients with AML after developing resistance to FLT3 inhibitors, which was identified as a common resistance pathway. We examined the concomitant inhibition of MEK-ERK1/2 and FLT3 as a strategy to overcome drug-resistance, finding that the MEK inhibitor trametinib remained potent in TKI-resistant cells and exerted strong synergy when combined with the TKI midostaurin in cells with mutated and wild-type FLT3. Importantly, this combination was not toxic to CD34+ cells from healthy donors, but produced survival improvements in vivo when compared with single therapy groups. Thus, our data point to trametinib plus midostaurin as a potentially beneficial therapy in patients with AML.
Highlights
FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML)
ERK1/2 pathway is activated in tyrosine kinase inhibitors (TKIs)-treated FLT3-mutated patients
Whole exome sequencing was used to confirm the absence of mutations in genes related to the main FLT3 downstream signaling pathways (ERK1/2, PI3K/AKT, and JAK/STAT)
Summary
FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several tyrosine kinase inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence of drug-resistance. A large phase III study demonstrated the efficacy of sorafenib in the upfront setting of young patients with AML, with superior www.nature.com/scientificreports event-free survival, relapse-free survival, and leukemia-free survival in the sorafenib arm[13] Another relevant TKI is midostaurin, which inhibits FLT3 and exhibits antiproliferative effects in mutant and wild-type (WT) FLT3 cells[14]. Midostaurin is the only FLT3 inhibitor approved in combination with intensive chemotherapy for adult patients with AML exhibiting activating FLT3 mutations[10] Despite these encouraging results, all of the TKIs tested so far have failed to show an efficient response in AML when used as a single drug[8,9], and either did not generate a sufficient initial response, or failed to sustain therapeutic benefits because of secondary resistance[11]. Concomitant blockade of ERK1/2 and FLT3 signaling pathways may provide clinical benefit for the treatment of a subset of patients with AML, as previously suggested[16,21,22]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
