TY - JOUR
T1 - Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia
AU - Nii, Takenobu
AU - Prabhu, Varun V.
AU - Ruvolo, Vivian
AU - Madhukar, Neel
AU - Zhao, Ran
AU - Mu, Hong
AU - Heese, Lauren
AU - Nishida, Yuki
AU - Kojima, Kensuke
AU - Garnett, Mathew J.
AU - McDermott, Ultan
AU - Benes, Cyril H.
AU - Charter, Neil
AU - Deacon, Sean
AU - Elemento, Olivier
AU - Allen, Joshua E.
AU - Oster, Wolfgang
AU - Stogniew, Martin
AU - Ishizawa, Jo
AU - Andreeff, Michael
N1 - Publisher Copyright:
© 2019, Springer Nature Limited.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41375-019-0491-z
DO - 10.1038/s41375-019-0491-z
M3 - Article
C2 - 31127149
AN - SCOPUS:85066233698
SN - 0887-6924
VL - 33
SP - 2805
EP - 2816
JO - Leukemia
JF - Leukemia
IS - 12
ER -