Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia
Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia
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DOI：
10.1038/s41375-019-0491-z
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发表时间：
2019-12-01
期刊：
影响因子：
11.4
通讯作者：
Andreeff, Michael
中科院分区：
文献类型：
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作者：
Nii, Takenobu;Prabhu, Varun V.;Andreeff, Michael
吡普利酮是一类新型的抗肿瘤药物。在这里，我们报道了与第一代化合物ONC201相比，第二代吡普利酮ONC212具有高度增强的抗肿瘤活性。使用人类急性髓性白血病（AML）细胞系、原发性AML和正常骨髓（BM）样本进行的体外研究表明，ONC212在AML中具有显著的凋亡作用，但在正常骨髓细胞中没有，这表明了潜在的临床应用价值。据推测，吡普利酮参与G蛋白偶联受体（gpcr）和/或触发造血肿瘤细胞的综合应激反应。综合GPCR筛选发现ONC212是孤儿GPCR GPR132和Gaq信号的激活子，具有肿瘤抑制作用。GPR132的杂合敲除降低了ONC212的抗白血病作用。ONC212通过诱导综合应激反应诱导凋亡效应，并降低MCL-1的表达，MCL-1是ABT-199抑制BCL-2的已知抗性因子。口服ONC212抑制体内AML生长，提高异种移植小鼠的总体生存。此外，ONC212在NSG PDX模型中消除了患者源性AML细胞的移植能力，表明可能根除AML起始细胞，并且与ABT-199联合使用具有高度协同作用。总之，我们的结果表明ONC212是一种新的AML治疗剂。
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 Gaq 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.