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Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.

ABSTRACT: Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute myeloid leukemia (AML) lines OCIM2 and OCI/AML3 (both wild-type), and primary samples from patients with AML. We show that (a) APcK110 inhibits proliferation of the mastocytosis cell line HMC1.2 and the SCF-responsive cell line OCI/AML3 in a dose-dependent manner; (b) APcK110 is a more potent inhibitor of OCI/AML3 proliferation than the clinically used Kit inhibitors imatinib and dasatinib and at least as potent as cytarabine; (c) APcK110 inhibits the phosphorylation of Kit, Stat3, Stat5, and Akt in a dose-dependent fashion, showing activity of APcK110 on Kit and its downstream signaling pathways; (d) APcK110 induces apoptosis by cleavage of caspase-3 and poly(ADP-ribose) polymerase; and (e) APcK110 inhibits proliferation of primary AML blasts in a clonogenic assay but does not affect proliferation of normal colony-forming cells. Although APcK110 activity may partly depend on cytokine responsiveness (e.g., SCF) and not exclusively KIT mutation status, it remains a potent inhibitor of AML and mastocytosis cell lines and primary AML samples. APcK110 and similar compounds should be evaluated in clinical trials of patients with AML.

SUBMITTER: Faderl S

PROVIDER: S-EPMC4220548 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.

Faderl Stefan S Pal Ashutosh A Bornmann William W Albitar Maher M Maxwell David D Van Quin Q Peng Zhenghong Z Harris David D Liu Zhiming Z Hazan-Halevy Inbal I Kantarjian Hagop M HM Estrov Zeev Z

Cancer research 20090421 9

Kit is a membrane-bound tyrosine kinase and receptor for stem cell factor (SCF) with a crucial role in hematopoiesis. Mutations of KIT occur in almost half of patients with core-binding factor leukemias, in which they have been associated with worse outcome. Development of new compounds targeting Kit may therefore hold promise for therapy. We investigated the activity and mechanism of action of APcK110, a novel Kit inhibitor, in the mastocytosis cell line HMC1.2 (KITV560G and KITD816V), acute my ...[more]

PMID: 19383925

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Project description:IntroductionThe emergence of resistance to the highly successful BCL2-directed therapy is a major unmet need in acute myeloid leukemia (AML), an aggressive malignancy with poor survival rates. Towards identifying therapeutic options for AML patients who progress on BCL2-directed therapy, we studied a clinical-stage CDK7 inhibitor XL102, which is being evaluated in solid tumors (NCT04726332).Materials and methodsTo determine the anti-proliferative effects of XL102, we performed experiments including time-resolved fluorescence resonance energy transfer, target occupancy, cell cycle and apoptosis-based assays. We also included genetically characterized primary myeloid blasts from de novo and relapsed/refractory AML patients. For mechanistic studies, CRISPR/Cas9 mediated knockout of CDK7 and c-Myc and immunoblotting were performed. NOD/SCID orthotropic and subcutaneous AML xenografts were used to determine anti-leukemic effects. To assess the synergistic effects of XL102 with Venetoclax, we performed RNA sequencing and gene set enrichment analysis using Venetoclax sensitive and resistant model systems.ResultsXL102, a highly specific, orally bioavailable covalent inhibitor of CDK7. Inhibitory effect on CDK7 by XL102 in primary myeloid blasts (n = 54) was in nanomolar range (mean = 300 nM; range = 4.0-952 nM). XL102 treated AML cells showed a reduction in phosphorylation levels of Serine 2/5/7 at carboxy-terminal domain of RNA polymerase II. T-loop phosphorylation of CDK1(Thr161) and CDK2(Thr160) was inhibited by XL102 in dose-dependent manner leading to cell-cycle arrest. c-Myc downregulation and enhanced levels of p53 and p21 in XL102 treated cells were observed. Increased levels of p21 and activation of p53 by XL102 were mimicked by genetic ablation of CDK7, which supports that the observed effects of XL102 are due to CDK7 inhibition. XL102 treated AML xenografts showed remarkable reduction in hCD45 + marrow cells (mean = 0.60%; range = 0.04%-3.53%) compared to vehicle control (mean = 38.2%; range = 10.1%-78%), with corresponding increase in p53, p21 and decrease in c-Myc levels. The data suggests XL102 induces apoptosis in AML cells via CDK7/c-Myc/p53 axis. RNA-sequencing from paired Venetoclax-sensitive and Venetoclax-resistant cells treated with XL102 showed downregulation of genes involved in proliferation and apoptosis.ConclusionTaken together, XL102 with Venetoclax led to synergistic effects in overcoming resistance and provided a strong rationale for clinical evaluation of XL102 as a single agent and in combination with Venetoclax.

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Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.

Publications

Kit inhibitor APcK110 induces apoptosis and inhibits proliferation of acute myeloid leukemia cells.

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