Abstract B028: Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors

Abstract

Abstract Phosphodiesterase 3A (PDE3A) modulators are promising anticancer agents for tumors that coexpress PDE3A and Schlafen 12 (SLFN12), including sarcomas. The cytotoxic effect of these modulators is based on their ability to form a complex between PDE3A and SLFN12, and correlates with the expression levels of the two proteins. In cases where the two proteins are only moderately expressed, PDE3A modulator efficacy may remain poor and additional therapeutic options are needed. In this study, we investigated the combinatorial effects of a PDE3A modulator, anagrelide, with 526 other oncological compounds in two PDE3A and SLFN12 expressing liposarcoma cell lines (SA4 and GOT3). Both cell lines were responsive to PDE3A modulators, as expected. Interestingly, we found synergy with seven different drug classes that can be grouped based on their protein and protein family targets: Bcl-2l/Bcl-xL, HDAC, integrin α2 (ITGA2), mTOR, NEDD-activating enzyme E1 regulatory subunit proteins, and PAK. Additional detailed drug combination synergy studies in PDE3A modulator –sensitive liposarcoma, gastrointestinal stromal tumor, melanoma, and astrocytoma cell lines indicated a sensitizing effect of PDE3A modulators to Bcl-2/Bcl-xL inhibitors. These cell lines, excluding GOT3, showed no response to Bcl-2/Bcl-xL inhibitors otherwise. Furthermore, we discovered that the sensitization effect depends on the coexpression of PDE3A and SLFN12, and that cotreatment resulted in stronger activation of programmed cell death. Our findings suggest additional combinatorial opportunities between PDE3A modulators and inhibitors of key cancer pathways that could be explored for their therapeutic value. Citation Format: Kirsi L. J. Toivanen, Astrid Murumägi, Mariliina A. Arjama, Nanna J. Merikoski, Sami I. Salmikangas, Olli P. Kallioniemi, Tom O. Böhling, Harri J. Sihto. Phosphodiesterase 3A modulators sensitize tumor cells to Bcl-2/Bcl-xL inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B028.