Abstract 6867: Triplet combination of monzosertib, a potent CDC7 inhibitor, with DNMT and BCL2 inhibitors is highly active in human AML xenograft mouse models

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 has been reported in many cancers and is thought to promote abnormal proliferation of cancer cells. Thus, CDC7 has been recognized as a potential drug target for treating cancers.Monzosertib (AS-0141) is a potent, selective, orally bioavailable small molecule inhibitor of CDC7, currently under Phase I clinical study in patients with advanced, metastatic, relapsed or refractory malignancies. In the previous studies, we demonstrated that monzosertib exerted strong synergy effects with DNA methyltransferase inhibitor (DNMTi; azacitidine or decitabine) or BCL2 inhibitor (venetoclax) in human acute myeloid leukemia (AML) cell lines.In this study, we evaluated the antitumor efficacy of monzosertib, DNMTi and venetoclax “triplet” therapy in human AML xenograft models. Method: Fa-CI plot (the Chou-Talalay method) was used to assess combination effects of monzosertib with DNMTi and venetoclax in human AML cell lines. Effects of drug combination on cellular signaling pathway were examined by western blotting. In vivo antitumor activity of monzosertib alone or in triplet combination with DNMTi and venetoclax were evaluated in human AML tumor-bearing mice. Results: Triplet combination of monzosertib with DNMTi (azacitidine or decitabine) and venetoclax resulted in a synergistic effect on antiproliferative activity in human AML cell lines. Treatment of MV4-11 cells (human AML cell line) with the triplet combination significantly increased in γH2AX, a biomarker of cellular response to DNA damage (DNA double strand breaks). Combining monzosertib with DNMTi (azacitidine or decitabine) and venetoclax resulted in enhanced tumor growth inhibition in a MV4-11 xenograft mouse model without body weight loss. Conclusions: Monzosertib demonstrated significant synergistic activity in combination with DNMTi (azacitidine or decitabine) and venetoclax in both in vitro and in vivo human AML models. The triplet combination of monzosertib with DNMTi (azacitidine or decitabine) and venetoclax was well-tolerated in these mouse AML models, suggesting the triplet therapy of monzosertib combined with the standard of care (DNMTi plus venetoclax) for AML patients may provide a new therapeutic opportunity in AML. Citation Format: Hatsuo Furuichi, Hiroko Endo, Akinori Arimura, Yu Nishioka, Masaaki Sawa. Triplet combination of monzosertib, a potent CDC7 inhibitor, with DNMT and BCL2 inhibitors is highly active in human AML xenograft mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6867.