Dataset Information

ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3-ITD.

ABSTRACT: Bromodomain-containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β-catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β-catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co-treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010-resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3-inhibitor-resistant FLT3-ITD/tyrosine kinase domain mutations and AML cells without FLT3-ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3-ITD.

SUBMITTER: Qian Y

PROVIDER: S-EPMC10323884 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3-ITD.

Qian Yu Y Zhang Xiang X Mao Shihui S Wei Wenwen W Lin Xiangjie X Ling Qing Q Ye Wenle W Li Fenglin F Pan Jiajia J Zhou Yutong Y Zhao Yanchun Y Huang Xin X Huang Jiansong J Tong Hongyan H Sun Jie J Jin Jie J

Molecular oncology 20230121 7

Bromodomain-containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β-catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β-catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal e ...[more]

PMID: 36567628

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Project description:AXL receptor tyrosine kinase (AXL) upregulation mediates drug resistance in several types of human cancer and has become a therapeutic target worthy of exploration. The present study investigated AXL antigen expression and the effects of novel AXL-targeted agents in acute myeloid leukemia (AML) cells. AXL antigen expression in drug-sensitive and drug-resistant human AML cell lines, and AML blast cells from 57 patients with different clinical characteristics, was analyzed by flow cytometry and compared. Furthermore, the effects of the novel AXL antibody DAXL-88, antibody-drug conjugate DAXL-88-monomethyl auristatin E (MMAE), AXL small molecule inhibitor R428 and their combination with FMS-like tyrosine kinase 3 (FLT3) inhibitor quizartinib (AC220) in AML cells were analyzed by Cell Counting Kit-8 assay, flow cytometry and western blotting. The present study revealed that AXL antigen expression was upregulated in FLT3-internal tandem duplication (ITD)/tyrosine kinase domain mutation-positive (TKD)+ AML blast cells compared with FLT3-ITD/TKD- AML cells. Additionally, AXL antigen expression was markedly upregulated in the AC220-resistant FLT3-ITD+ MV4-11 cell line (MV4-11/AC220) and in FLT3 inhibitor-resistant blast cells from a patient with FLT3-ITD+ AML compared with parental sensitive cells. The AXL-targeted agents DAXL-88, DAXL-88-MMAE and R428 exhibited dose-dependent cytotoxic effects on FLT3-mutant AML cell lines (THP-1, MV4-11 and MV4-11/AC220) and blast cells from patients with FLT3-ITD+ AML. Combinations of AXL-targeted agents with AC220 exerted synergistic cytotoxic effects and induced apoptosis in MV4-11/AC220 cells and FLT3 inhibitor-resistant blast cells. The antileukemic effect of DAXL-88 and DAXL-88-MMAE may rely on their ability to block AXL, FLT3 and their downstream signaling pathways. The present study demonstrated the association between AXL antigen expression upregulation and drug resistance in FLT3-ITD+ AML, and proposed a method for overcoming FLT3 inhibitor resistance of FLT3-ITD+ AML using novel AXL-targeted agents.

Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

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Dataset Information

ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3-ITD.

Publications

ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3-ITD.

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