MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia

摘要: FMS-like tyrosine kinase 3 (FLT3) is a key driver of acute myeloid leukemia (AML). Several inhibitors (TKIs) targeting FLT3 have been evaluated clinically, but their effects are limited when used in monotherapy due to the emergence drug-resistance. Thus, better understanding drug-resistance pathways could be good strategy explore and evaluate new combinational therapies for AML. Here, we phosphoproteomics identify differentially-phosphorylated proteins patients with AML TKI resistance. We then studied resistance mechanisms vitro efficacy safety rational therapy vitro, ex vivo mice. Proteomic immunohistochemical studies showed sustained activation ERK1/2 bone marrow samples after developing inhibitors, which was identified as common pathway. examined concomitant inhibition MEK-ERK1/2 overcome drug-resistance, finding that MEK inhibitor trametinib remained potent TKI-resistant cells exerted strong synergy combined midostaurin mutated wild-type FLT3. Importantly, this combination not toxic CD34+ from healthy donors, produced survival improvements compared single groups. our data point plus potentially beneficial