Abstract 981: BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS)

Abstract

Abstract The AML treatment landscape has improved dramatically in the past decade, with improved objective response rates and overall survival after treatment with newly approved targeted therapies. BCL-2 inhibition combined with a hypomethylating agent or low-dose cytosine arabinoside (Ara-C) is also effective in previously untreated elderly patients who are not candidates for standard induction therapy. However, the effect of BCL-2 inhibition is commonly weakened when tumor cells upregulate antiapoptotic protein MCL-1 to escape apoptosis. Thus, combination therapy is introduced to suppress MCL-1 levels. HHT (omacetaxine mepesuccinate) has been widely used in Chinese patients with AML for 30 years. As an inhibitor of protein synthesis, HHT decreases MCL-1. This study investigated the effect of combining clinical stage BCL-2 selective inhibitor APG-2575 with HHT in AML and MDS cells, as well as murine xenograft tumor models. In AML (MV-4-11, OCI-AML-3) and MDS (SKM-1) cell lines, single-agent HHT exerted stronger antiproliferative and apoptogenic activities compared to APG-2575 (as assessed by Cell Titer Glo assay or flow cytometry). When combined, these treatments synergistically inhibited cellular proliferation and induced apoptosis. In a mouse xenograft tumor model derived from MV-4-11 cells, APG-2575 demonstrated limited antitumor activity, with a T/C (Treated/Control tumor volume %) value of 63% whereas HHT showed stronger activity, with T/C equal to 30%. Most importantly, these antitumor effects were potentiated when APG-2575 and HHT were combined, yielding a T/C value of 3% and partial regression in all treated tumors. Mechanistically, BCL-2 inhibition with APG-2575 decreased BCL-2:BIM complexes and but increased MCL-1:BIM complexes, as liberated BIM was re-sequestered by MCL-1. On the other hand, concomitant treatment with HHT abolished induction of MCL-1:BIM complexes. Besides BIM complexes, MCL-1:PUMA and MCL-1:BAK pairings also decreased after exposure to HHT. The decrease in MCL-1 complex coincided with its downregulation at protein levels. Thus, under such an MCL-1-supressed condition facilitated by HHT treatment, the freed proapoptotic proteins (BIM, PUMA, BAK) more potently manifested apoptotic signals triggered by APG-2575. In summary, APG-2575 synergizes with HHT to potentiate antitumor activity in preclinical models of AML/MDS. HHT suppresses MCL-1 protein, preventing or abolishing formation of MCL-1:BIM, MCL-1:PUMA, and MCL-1:BAK complexes, and hence allowing prodeath proteins to fully engage in tumor cell apoptosis induction. Our results provide scientific rationale for clinical development of APG-2575 plus HHT in patients with AML/MDS. Citation Format: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Tao Rong, Qixin Wang, Jing Deng, Dajun Yang, Yifan Zhai. BCL-2 inhibitor APG-2575 and homoharringtonine (HHT) synergistically induces apoptosis and inhibits tumor growth in preclinical models of acute myeloid leukemia and myelodysplastic syndromes (AML/MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 981.