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Ref Type Journal Article
PMID (26822154)
Authors Zhang W, Borthakur G, Gao C, Chen Y, Mu H, Ruvolo VR, Nomoto K, Zhao N, Konopleva M, Andreeff M
Title The Dual MEK/FLT3 Inhibitor E6201 Exerts Cytotoxic Activity against Acute Myeloid Leukemia Cells Harboring Resistance-Conferring FLT3 Mutations.
Journal Cancer research
Vol 76
Issue 6
Date 2016 Mar 15
URL
Abstract Text Fms-like tyrosine kinase 3 (FLT3) inhibition has elicited encouraging responses in acute myeloid leukemia (AML) therapy. Unfortunately, unless combined with a bone marrow transplant, disease relapse is frequent. In addition to the acquired point mutations in the FLT3 kinase domain that contribute to FLT3 inhibitor resistance, MEK/ERK signaling is persistently activated in AML cells even when FLT3 phosphorylation is continually suppressed. Thus, concomitant targeting of FLT3 and MAPK may potentially exert synergistic activity to counteract the resistance of AML cells to FLT3-targeted therapy. In this study, we investigated the antileukemia activity of a MEK1 and FLT3 dual inhibitor, E6201, in AML cells resistant to FLT3 inhibition. We found that E6201 exerted profound apoptogenic effects on AML cells harboring resistance-conferring FLT3 mutations. This activity appeared to be p53 dependent, and E6201-induced cytotoxicity was retained under hypoxic culture conditions and during coculture with mesenchymal stem cells that mimic the AML microenvironment. Furthermore, E6201 markedly reduced leukemia burden and improved the survival of mice in a human FLT3-mutated AML model. Collectively, our data provide a preclinical basis for the clinical evaluation of E6201 in AML patients harboring FLT3 mutations, including those who relapse following FLT3-targeted monotherapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins leukemia sensitive E6201 Preclinical - Cell line xenograft Actionable In a preclinical study, E6201 induced growth inhibition and apoptosis in leukemia cell lines harboring FLT3 internal tandem duplications (ITD) and reduced tumor burden in xenograft models (PMID: 26822154). 26822154
FLT3 mutant acute myeloid leukemia sensitive E6201 Preclinical Actionable In a preclinical study, acute myeloid leukemia cell lines harboring FLT3 mutations demonstrated increased sensitivity to E6201 induced growth inhibition and apoptosis in culture compared to FLT3 wild-type cells (PMID: 26822154). 26822154
FLT3 D835G leukemia sensitive E6201 Preclinical Actionable In a preclinical study, E6201 inhibited proliferation and induced apoptosis in FLT3 inhibitor-resistant leukemia cell lines over expressing FLT3 D835G in culture (PMID: 26822154). 26822154
FLT3 exon 14 ins FLT3 Y842C leukemia sensitive E6201 Preclinical Actionable In a preclinical study, E6201 inhibited proliferation and induced apoptosis in FLT3 inhibitor-resistant leukemia cell lines harboring FLT3 Y842C in addition to FLT3 internal tandem duplications (ITD) in culture (PMID: 26822154). 26822154
FLT3 exon 14 ins FLT3 F691L leukemia sensitive E6201 Preclinical Actionable In a preclinical study, E6201 inhibited proliferation and induced apoptosis in FLT3 inhibitor-resistant leukemia cell lines harboring FLT3 F691L in addition to FLT3 internal tandem duplications (ITD) in culture (PMID: 26822154). 26822154
FLT3 D835Y acute myeloid leukemia sensitive E6201 Preclinical - Cell culture Actionable In a preclinical study, E6201 induced apoptosis in blast samples derived from acute myeloid leukemia patients harboring FLT3 D835Y in culture (PMID: 26822154). 26822154
FLT3 D835Y leukemia sensitive E6201 Preclinical Actionable In a preclinical study, E6201 inhibited proliferation and induced apoptosis in FLT3 inhibitor-resistant leukemia cell lines over expressing FLT3 D835Y in culture (PMID: 26822154). 26822154
FLT3 exon 14 ins acute myeloid leukemia sensitive E6201 Preclinical - Cell culture Actionable In a preclinical study, E6201 induced apoptosis in blast samples derived from acute myeloid leukemia patients harboring FLT3 internal tandem duplications (ITD) in culture (PMID: 26822154). 26822154
FLT3 D835G acute myeloid leukemia sensitive E6201 Preclinical - Cell culture Actionable In a preclinical study, E6201 induced apoptosis in blast samples derived from acute myeloid leukemia patients harboring FLT3 D835G in culture (PMID: 26822154). 26822154
FLT3 exon 14 ins FLT3 N676D FLT3 Y842C leukemia sensitive E6201 Preclinical Actionable In a preclinical study, E6201 inhibited proliferation and induced apoptosis in FLT3 inhibitor-resistant leukemia cell lines harboring FLT3 N676D and Y842C in addition to FLT3 internal tandem duplications (ITD) in culture (PMID: 26822154). 26822154