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

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, an...

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Veröffentlicht in:	Leukemia Jg. 33; H. 12; S. 2805 - 2816
Hauptverfasser:	Nii, Takenobu, Prabhu, Varun V., Ruvolo, Vivian, Madhukar, Neel, Zhao, Ran, Mu, Hong, Heese, Lauren, Nishida, Yuki, Kojima, Kensuke, Garnett, Mathew J., McDermott, Ultan, Benes, Cyril H., Charter, Neil, Deacon, Sean, Elemento, Olivier, Allen, Joshua E., Oster, Wolfgang, Stogniew, Martin, Ishizawa, Jo, Andreeff, Michael
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 01.12.2019 Nature Publishing Group
Schlagworte:	13/106 13/2 13/31 14/1 38/109 38/77 42/34 631/67/1059 692/308/153 82/80 Acute myeloid leukemia Animals Anticancer properties Antineoplastic Agents - pharmacology Antitumor activity Antitumor agents Apoptosis - drug effects Bcl-2 protein Biomarkers Bone marrow Cancer Research Cell Cycle - drug effects Cell Cycle Proteins - agonists Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Cellular stress response Chemical compounds Critical Care Medicine Disease Models, Animal G protein-coupled receptors G proteins Gene Expression Regulation, Leukemic Hematology Humans Imidazoles - chemistry Imidazoles - pharmacology Intensive Internal Medicine Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - etiology Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Mcl-1 protein Medicine Medicine & Public Health Membrane proteins Mice Molecular Structure Myeloid leukemia Oncology Oral administration Pharmacology Proteins Pyridines - chemistry Pyridines - pharmacology Pyrimidines - chemistry Pyrimidines - pharmacology Receptors Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Resistance factors Stress response Stress, Physiological - genetics Transcriptional Activation Treatment Outcome Tumor cell lines Tumor cells Tumor suppressor genes Xenograft Model Antitumor Assays Xenografts
ISSN:	0887-6924, 1476-5551, 1476-5551
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 TN, JI, VVP, KK, JEA, WO, MS and MA conceived and designed the study. TN, JI, VVP, NM, VR, LH, RZ, YN, SD, JEA and HM acquired the data. TN, JI, VVP, YN, NM, KK, MJG, UM, CHB, NC, OE, JEA, MS and MA analyzed and interpreted the data. TN, JI, VVP, KK, JEA, MS, WO and MA wrote, reviewed and/or revised the manuscript. Corresponding authors: Michael Andreeff MD, PhD (mandreef@mdanderson.org), Jo Ishizawa, MD, PhD (JIshizawa@mdanderson.org), Section of Molecular Hematology and Therapy, Department of Leukemia, Unit 448, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Both authors contributed equally to this work. Author contributions
ISSN:	0887-6924 1476-5551 1476-5551
DOI:	10.1038/s41375-019-0491-z