Reference Detail

Ref Type

Journal Article

PMID

(31751472)

Authors

Beeharry N, Landrette S, Gayle S, Hernandez M, Grotzke JE, Young PR, Beckett P, Zhang X, Carter BZ, Andreeff M, Halene S, Xu T, Rothberg J, Lichenstein H

Title

LAM-003, a new drug for treatment of tyrosine kinase inhibitor-resistant FLT3-ITD-positive AML.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood advances	3	22	2019 Nov 26	3661-3673	Blood Adv

URL

Abstract Text

Acute myeloid leukemias (AML) harboring a constitutively active internal tandem duplication (ITD) mutation in the FMS-like kinase tyrosine kinase (FLT3) receptor are associated with poor patient prognosis. Despite initial clinical responses to FLT3 kinase inhibitors, patients eventually relapse. Mechanisms of resistance include the acquisition of secondary FLT3 mutations and protective stromal signaling within the bone marrow niche. Here we show that LAM-003, a prodrug of the heat shock protein 90 inhibitor LAM-003A, has cytotoxic activity against AML cell lines and primary samples harboring FLT3-ITD. LAM-003 regressed tumors in an MV-4-11 xenograft mouse model and extended survival in a MOLM-13 systemic model. LAM-003 displayed synergistic activity with chemotherapeutic drugs and FLT3 inhibitors, with the most robust synergy being obtained with venetoclax, a BCL-2 inhibitor. This finding was verified in a MOLM-13 systemic survival model in which the combination significantly prolonged survival compared with the single agents. Importantly, LAM-003 exhibited equipotent activity against FLT3 inhibitor-resistant mutants of FLT3, such as D835 or F691, in cytotoxic and FLT3 degradation assays. LAM-003 also retained potency in AML cells grown in stromal-conditioned media that were resistant to FLT3 inhibitors. Lastly, a genome-wide CRISPR screen revealed epigenetic regulators, including KDM6A, as determinants of LAM-003 sensitivity in AML cell lines, leading to the discovery of synergy with an EZH2 inhibitor. Collectively, these preclinical findings support the use of LAM-003 in FLT3-ITD patients with AML who no longer respond to FLT3 inhibitor therapy either as a single agent or in combination with drugs known to be active in 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
LAM-003	LAM-003	6	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LAM-003		LAM003\|LAM 003	HSP90 Inhibitor 35	LAM-003 is a prodrug that is metabolized by esterases into the active HSP90 inhibitor drug, LAM-003A, which potentially induces cytotoxicity, and inhibits viability and tumor growth (PMID: 31751472).

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	acute myeloid leukemia	sensitive	GSK690693 + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, GSK690693 and Venclexta (venetoclax) combination treatment synergistically induced cell death of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	LAM-003 + Venetoclax	Preclinical - Patient cell culture	Actionable	In a preclinical study, LAM-003 and Venclexta (venetoclax) combination treatment synergistically induced cell death, and inhibited viability of acute myeloid leukemia cell lines and patient-derived cells harboring FLT3 internal tandem duplication (ITD) in culture, and increased survival in a cell line xenograft model (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	A-1210477 + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, A-1210477 and Venclexta (venetoclax) combination treatment synergistically inhibited viability of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	resistant	Tandutinib	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid cell line harboring FLT3 internal tandem duplication (ITD) and FLT3 D835Y demonstrated resistance to Tandutinib (CT53518) treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	resistant	Sorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid cell line harboring FLT3 internal tandem duplication (ITD) and FLT3 D835Y did not demonstrate sensitivity to Nexavar (sorafenib) treatment in culture (PMID: 31751472).	31751472
FLT3 D835Y	acute myeloid leukemia	predicted - sensitive	LAM-003	Preclinical - Patient cell culture	Actionable	In a preclinical study, patient-derived acute myeloid leukemia cells harboring FLT3 D835Y demonstrated sensitivity to LAM-003 treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	LAM-003	Preclinical - Patient cell culture	Actionable	In a preclinical study, LAM-003 treatment inhibited colony formation, and reduced viability of acute myeloid cell lines harboring FLT3 internal tandem duplication (ITD) in the presence of stromal factors that confer resistance to Xospata (gilteritinib) and Crenolanib, and induced apoptosis in patient-derived cells in culture, and induced tumor regression, and increased survival in cell line xenograft models (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Tandutinib	Preclinical - Cell culture	Actionable	In a preclinical study, Tandutinib (CT53518) treatment inhibited viability of an acute myeloid leukemia cell line harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	LAM-003 + Tazemetostat	Preclinical - Cell culture	Actionable	In a preclinical study, LAM-003 and Tazemetostat (EPZ-6438) combination treatment synergistically inhibited viability of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Midostaurin	Preclinical - Cell culture	Actionable	In a preclinical study, an acute myeloid leukemia cell line harboring a FLT3 internal tandem duplication (ITD) demonstrated sensitivity to Rydapt (midostaurin) treatment, but when co-cultured with human stromal cells, demonstrated resistance to Rydapt (midostaurin) treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins FLT3 D835Y	acute myeloid leukemia	sensitive	LAM-003	Preclinical - Patient cell culture	Actionable	In a preclinical study, LAM-003 treatment inhibited viability of an acute myeloid leukemia cell line and patient-derived cells harboring FLT3 internal tandem duplication (ITD) and FLT3 D835Y in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	Advanced Solid Tumor	sensitive	LAM-003	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3 internal tandem duplication (ITD) demonstrated sensitivity to LAM-003 treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Daunorubicin + LAM-003	Preclinical - Cell culture	Actionable	In a preclinical study, LAM-003 and Cerubidine (daunorubicin) combination treatment synergistically reduced viability of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 D835X	acute myeloid leukemia	predicted - sensitive	LAM-003	Preclinical - Patient cell culture	Actionable	In a preclinical study, patient-derived acute myeloid leukemia cells harboring FLT3 D835X demonstrated sensitivity to LAM-003 treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins FLT3 F691L	Advanced Solid Tumor	sensitive	LAM-003	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3 internal tandem duplication (ITD) and FLT3 F691L demonstrated sensitivity to LAM-003 treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Cytarabine + LAM-003	Preclinical - Cell culture	Actionable	In a preclinical study, LAM-003 and Cytosar-U (cytarabine) combination treatment synergistically reduced viability of an acute myeloid leukemia cell line harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	Advanced Solid Tumor	sensitive	Crenolanib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing FLT3 internal tandem duplication (ITD) demonstrated sensitivity to Crenolanib treatment in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	Gilteritinib + LAM-003	Preclinical - Cell culture	Actionable	In a preclinical study, LAM-003 and Xospata (gilteritinib) combination treatment reduced viability of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472
FLT3 exon 14 ins	acute myeloid leukemia	sensitive	MK2206 + Venetoclax	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 and Venclexta (venetoclax) combination treatment synergistically induced cell death of acute myeloid leukemia cell lines harboring FLT3 internal tandem duplication (ITD) in culture (PMID: 31751472).	31751472