Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia.

Autor: Nii T; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Prabhu VV; Oncoceutics, Inc., Philadelphia, PA, USA., Ruvolo V; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Madhukar N; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA., Zhao R; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mu H; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Heese L; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Nishida Y; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kojima K; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Saga University, Saga, Japan., Garnett MJ; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK., McDermott U; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge, UK., Benes CH; Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., Charter N; DiscoverX Corporation, Fremont, CA, USA., Deacon S; DiscoverX Corporation, Fremont, CA, USA., Elemento O; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY, USA., Allen JE; Oncoceutics, Inc., Philadelphia, PA, USA., Oster W; Oncoceutics, Inc., Philadelphia, PA, USA., Stogniew M; Oncoceutics, Inc., Philadelphia, PA, USA., Ishizawa J; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. JIshizawa@mdanderson.org., Andreeff M; Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mandreef@mdanderson.org.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2019 Dec; Vol. 33 (12), pp. 2805-2816. Date of Electronic Publication: 2019 May 24.
DOI: 10.1038/s41375-019-0491-z
Abstrakt: Imipridones constitute a novel class of antitumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased antitumor activity compared to the first-generation compound ONC201. In vitro studies using human acute myeloid leukemia (AML) cell lines, primary AML, and normal bone marrow (BM) samples demonstrate that ONC212 exerts prominent apoptogenic effects in AML, but not in normal BM cells, suggesting potential clinical utility. Imipridones putatively engage G protein-coupled receptors (GPCRs) and/or trigger an integrated stress response in hematopoietic tumor cells. Comprehensive GPCR screening identified ONC212 as activator of an orphan GPCR GPR132 and Gαq signaling, which functions as a tumor suppressor. Heterozygous knock-out of GPR132 decreased the antileukemic effects of ONC212. ONC212 induced apoptogenic effects through the induction of an integrated stress response, and reduced MCL-1 expression, a known resistance factor for BCL-2 inhibition by ABT-199. Oral administration of ONC212 inhibited AML growth in vivo and improved overall survival in xenografted mice. Moreover, ONC212 abrogated the engraftment capacity of patient-derived AML cells in an NSG PDX model, suggesting potential eradication of AML initiating cells, and was highly synergistic in combination with ABT-199. Collectively, our results suggest ONC212 as a novel therapeutic agent for AML.
Databáze: MEDLINE
Externí odkaz: