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Ref Type Journal Article
PMID (33268594)
Authors Jeon JY, Buelow DR, Garrison DA, Niu M, Eisenmann ED, Huang KM, Zavorka Thomas ME, Weber RH, Whatcott CJ, Warner SL, Orwick SJ, Carmichael B, Stahl E, Brinton LT, Lapalombella R, Blachly JS, Hertlein E, Byrd JC, Bhatnagar B, Baker SD
Title TP-0903 is active in models of drug-resistant acute myeloid leukemia.
Journal JCI insight
Vol 5
Issue 23
Date 2020 Dec 03
URL
Abstract Text Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment-mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3-ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL-PTD, ASXL1, SRSF2, and WT1, which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.

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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 D835H hematologic cancer sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of transformed cells expressing FLT3 D835H in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia sensitive Dubermatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Dubermatinib (TP-0903) treatment resulted in cell cycle arrest and apoptosis, induced differentiation, and inhibited growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and FLT3 D835Y in culture, and reduced tumor growth and increased survival in cell line xenograft models (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - resistant Midostaurin Preclinical Actionable In a preclinical study, Rydapt (midostaurin) failed to inhibit growth of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - sensitive Crenolanib Preclinical - Cell culture Actionable In a preclinical study, high dosage Crenolanib (CP-868596) treatment resulted in reduced viability of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins FLT3 D835Y hematologic cancer sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of transformed cells expressing a FLT3-ITD mutation and FLT3 D835Y in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins FLT3 D835H hematologic cancer sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of transformed cells expressing a FLT3-ITD mutation and FLT3 D835H in culture (PMID: 33268594). 33268594
FLT3 D835Y hematologic cancer sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of transformed cells expressing FLT3 D835Y in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins hematologic cancer sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of transformed cells expressing a FLT3-ITD mutation in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins FLT3 D835Y acute myeloid leukemia predicted - sensitive Gilteritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Xospata (gilteritinib) treatment inhibited growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and FLT3 D835Y in culture, and reduced tumor growth and increased survival in cell line xenograft models (PMID: 33268594). 33268594
FLT3 exon 14 ins FLT3 F691L hematologic cancer sensitive Dubermatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Dubermatinib (TP-0903) treatment decreased phosphorylation of Flt3 and Stat5 and inhibited growth of transformed cells expressing a FLT3-ITD mutation and FLT3 F691L in culture, and reduced peripheral blood tumor burden in cell line xenograft models (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - resistant Quizartinib Preclinical Actionable In a preclinical study, Vanflyta (Quizartinib) failed to inhibit growth of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - sensitive Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, high dosage Xospata (gilteritinib) treatment resulted in reduced viability and colony formation of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins NRAS G12D acute myeloid leukemia predicted - sensitive Dubermatinib Preclinical - Cell culture Actionable In a preclinical study, Dubermatinib (TP-0903) inhibited growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and NRAS G12D in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - sensitive Dubermatinib Preclinical Actionable In a preclinical study, Dubermatinib (TP-0903) treatment inhibited growth and colony formation of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture, and increased survival in mouse models (PMID: 33268594). 33268594
FLT3 exon 14 ins acute myeloid leukemia sensitive Dubermatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Dubermatinib (TP-0903) treatment resulted in cell cycle arrest and apoptosis, induced differentiation, and inhibited growth of acute myeloid leukemia cell lines harboring a FLT3-ITD mutation in culture, and reduced tumor growth and increased survival in cell line xenograft models (PMID: 33268594). 33268594
FLT3 exon 14 ins IDH2 R140Q acute myeloid leukemia predicted - resistant Sorafenib Preclinical Actionable In a preclinical study, Nexavar (sorafenib) failed to inhibit growth of cells isolated from a transgenic mouse model of acute myeloid leukemia harboring a FLT3-ITD mutation and IDH2 R140Q in culture (PMID: 33268594). 33268594
FLT3 exon 14 ins NRAS G12D acute myeloid leukemia predicted - resistant Gilteritinib Preclinical - Cell culture Actionable In a preclinical study, Xospata (gilteritinib) failed to inhibit growth of acute myeloid leukemia cells harboring a FLT3-ITD mutation and NRAS G12D in culture (PMID: 33268594). 33268594