Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
JCI insight	5	23	2020 Dec 03		JCI Insight

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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
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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Showing 1 to 17 of 17 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 FLT3 D835Y	acute myeloid leukemia	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 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 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 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 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 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 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 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
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 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 - 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 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

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