A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors.

Autor:	Takaki EO; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Kiyono K; Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan., Obuchi Y; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Yamauchi T; Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan., Watanabe T; Department of Drug Modality Development, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Matsumoto H; Department of Drug Modality Development, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Karimine M; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Kuniyoshi Y; Office of Bioinformatics, Department of Drug Discovery Strategy, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Nishikori S; Department of Drug Modality Development, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Yokoyama F; Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., Otsu, Japan., Nishimori H; Department of Drug Modality Development, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Nabeshima H; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan., Nakamura K; Department of Medical Innovations, Osaka Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Minoh, Japan.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 15; Vol. 30 (16), pp. 3603-3621.
DOI:	10.1158/1078-0432.CCR-24-0096
Abstrakt:	Purpose: Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor with KIT or PDGFRA driver mutations, is typically treated with tyrosine kinase inhibitors (TKI). However, resistance to TKIs due to secondary mutations is a common challenge in advanced GISTs. In addition, there are currently no effective therapies for several other molecular subtypes, such as succinate dehydrogenase-deficient GISTs. Therefore, novel therapeutic strategies are needed. Experimental Design: To address this need, we tested the efficacy of a novel non-TKI compound, OPB-171775, using patient-derived xenograft models of GISTs. In parallel, we sought to elucidate the mechanism of action of the compound. Results: Our study revealed that OPB-171775 exhibited significant efficacy against GISTs regardless of their KIT mutation status by inducing complex formation between phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12), which are highly expressed in GISTs, leading to SLFN12 RNase-mediated cell death. Furthermore, we identified the activation of general control non-derepressible 2 and its downstream response as an effector pathway of SLFN12 in mediating anticancer activity and revealed potential pharmacodynamic markers. Conclusions: These findings suggest that OPB-171775, with its significant efficacy, could potentially serve as a novel and effective treatment option for advanced GISTs, particularly those resistant to TKIs. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu