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Acute myeloid leukemia

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

Abstract

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.

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Acknowledgements

This work was supported in part by grants from the National Institutes of Health (P01CA055164), Cancer Prevention Research Institute of Texas (CPRIT, RP121010), the Paul and Mary Haas Chair in Genetics (to MA), the MD Anderson’s Cancer Center Support Grant (CA016672) (to MA); the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and International Research Fund for Subsidy of Kyushu University School of Medicine Alumni (to TN); NIH Leukemia SPORE Career Enhancement Programs (to JI); and Oncoceutics, Inc. GDSC screening was supported by a grant from the Wellcome Trust (102696).

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TN, JI, VVP, KK, JEA, WO, MS, and MA conceived and designed the study and wrote, reviewed, and/or revised the manuscript. 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.

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Correspondence to Jo Ishizawa or Michael Andreeff.

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VVP, JEA, WO, and MS are employees and stockholders of Oncoceutics. MA is a member of the scientific advisory board of Oncoceutics and stock holder.

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Nii, T., Prabhu, V.V., Ruvolo, V. et al. Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia. Leukemia 33, 2805–2816 (2019). https://doi.org/10.1038/s41375-019-0491-z

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