Synergistic Effect of the CDC7 Inhibitor, Monzosertib (AS-0141) with Current Therapies in AML Models

Hiroko Endo,Hatsuo Furuichi,Akinori Arimura,Yu Nishioka,Masaaki Sawa

Cancer Research（2024）

1Carna Biosciences | 2CarnaBio USA

Cited 0|Views8

Abstract

Abstract Introduction: Cell division cycle 7 (CDC7) is a highly conserved serine-threonine kinase that plays an important role in the initiation of DNA replication and cell cycle progression. Aberrant expression of CDC7 have been reported to cause uncontrolled proliferation of many cancer types, suggesting that CDC7 inhibitors may provide a great potential for the development of novel therapy for cancers. Monzosertib (AS-0141) is a potent, selective, orally bioavailable small molecule inhibitor of CDC7, and is currently being evaluated in Phase I study for the treatment of solid tumors. In a preclinical cancer cell panel study, monzosertib showed strong antiproliferative activities against a variety of cancer types, and acute myeloid lymphoma (AML) cell lines were found to be the most sensitive to monzosertib. As a single agent, treatment with monzosertib accumulates DNA damage in cancer cells and induces cell death. In this study, we aimed to investigate the antitumor effects of monzosertib alone and in combination with other anticancer drugs in AML models. Method: Antiproliferative activity of monzosertib was examined against a panel of 35 human cancer cell lines of various cancer types. DNA metyltransferase (DNMT) inhibitors (azacitidine or decitabine) and BCL2 inhibitor (venetoclax) were evaluated for their synergistic/antagonistic effects in combination with monzosertib against human AML cell lines (THP-1, HL-60, MV4-11, MOLM-14, TF-1, U-937 and NOMO-1). The combination index (CI) was calculated using the Chou-Talalay method. Flow cytometry assay was used to analyze apoptosis. To evaluate the in vivo efficacy, tumor-bearing mice were treated with monzosertib alone or in combination with venetoclax. Results: The combination of monzosertib with azacitidine, decitabine, or venetoclax resulted in a significant synergistic antiproliferative effects against AML cell lines in vitro. The flow cytometry assay indicated that azacitidine combination induced apoptosis and increased cell death in THP-1 cells. In vivo, oral administration of monzosertib demonstrated robust in vivo antitumor efficacy in a MV4-11 tumor bearing xenograft mouse model, both as a single agent and in combination with venetoclax. Conclusions: Monzosertib, a selective CDC7 inhibitor, demonstrated strong antiproliferative activity against human AML cell lines, both as a single agent and in combination with standard therapies. Monzosertib exerts synergistic antitumor effect with venetoclax in a human AML xenograft mouse model. These results suggest that monzosertib has a potential to enhance the antitumor efficacy of standard of care agents for AML patients. Citation Format: Hiroko Endo, Hatsuo Furuichi, Akinori Arimura, Yu Nishioka, Masaaki Sawa. Synergistic effect of the CDC7 inhibitor, monzosertib (AS-0141) with current therapies in AML models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5714.

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【要点】：研究显示CDC7抑制剂Monzosertib（AS-0141）单独使用及与现有治疗联合使用在AML模型中具有显著的抗肿瘤效果，具有协同增效。

【方法】：通过检测Monzosertib对35种人类癌细胞系的抗增殖活性，并评估其与DNA甲基转移酶抑制剂（azacitidine或decitabine）及BCL2抑制剂venetoclax联用的协同/拮抗效应。

【实验】：采用流式细胞术分析细胞凋亡，并在MV4-11移植瘤小鼠模型中评估了Monzosertib单独及联合venetoclax的体内抗肿瘤效果。实验使用的数据集为人类AML细胞系（THP-1, HL-60, MV4-11, MOLM-14, TF-1, U-937和NOMO-1）。结果显示，Monzosertib与上述药物联用对AML细胞系显示出显著的协同抗增殖效应，且在体内实验中同样有效。