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

Imipridones constitute a novel class of anti-tumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased anti-tumor activity compared to the first-generation compound ONC201. In vitro studies using human acute myeloid leukemia (AML) cell lines, primary AML,...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874902/
https://www.ncbi.nlm.nih.gov/pubmed/31127149
http://dx.doi.org/10.1038/s41375-019-0491-z
Descripción
Sumario:Imipridones constitute a novel class of anti-tumor agents. Here, we report that a second-generation imipridone, ONC212, possesses highly increased anti-tumor 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 anti-leukemic 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.