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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, et al. Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med. 2013;5:171ra17. https://doi.org/10.1126/scitranslmed.3004828
Allen JE, Kline CLB, Prabhu VV, Wagner J, Ishizawa J, Madhukar N, et al. Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget. 2016;7:74380–92. https://doi.org/10.18632/oncotarget.11814
Arrillaga-Romany I, Chi AS, Allen JE, Oster W, Wen PY, Batchelor TT. A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget. 2017;8:79298–304. https://doi.org/10.18632/oncotarget.17837
Stein MN, Bertino JR, Kaufman HL, Mayer T, Moss R, Silk A, et al. First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. Clin Cancer Res. 2017;23:4163–9. https://doi.org/10.1158/1078-0432.ccr-16-2658
Kline CLB, Ralff MD, Lulla AR, Wagner JM, Abbosh PH, Dicker DT. et al. Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia. 2018;20:80–91. https://doi.org/10.1016/j.neo.2017.10.002
Kline CL, Van den Heuvel AP, Allen JE, Prabhu VV, Dicker DT, El-Deiry WS. ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2alpha kinases. Sci Signal. 2016;9:ra18. https://doi.org/10.1126/scisignal.aac4374
Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, et al. ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal. 2016;9:ra17. https://doi.org/10.1126/scisignal.aac4380
Allen JE, Crowder R, El-Deiry WS. First-in-class small molecule ONC201 induces DR5 and cell death in tumor but not normal cells to provide a wide therapeutic index as an anti-cancer agent. PLoS ONE 2015;10:e0143082. https://doi.org/10.1371/journal.pone.0143082
Dorsam RT, Gutkind JS. G-protein-coupled receptors and cancer. Nat Rev Cancer. 2007;7:79–94. https://doi.org/10.1038/nrc2069
Lynch JR, Wang JY. G protein-coupled receptor signaling in stem cells and cancer. Int J Mol Sci. 2016;17:707. https://doi.org/10.3390/ijms17050707
Lappano R, Maggiolini M. G protein-coupled receptors: novel targets for drug discovery in cancer. Nat Rev Drug Discov. 2011;10:47–60. https://doi.org/10.1038/nrd3320
Jones LH, Bunnage ME. Applications of chemogenomic library screening in drug discovery. Nat Rev Drug Discov. 2017;16:285–96. https://doi.org/10.1038/nrd.2016.244
Wagner J, Kline CL, Pottorf RS, Nallaganchu BR, Olson GL, Dicker DT, et al. The angular structure of ONC201, a TRAIL pathway-inducing compound, determines its potent anti-cancer activity. Oncotarget. 2014;5:12728–37. https://doi.org/10.18632/oncotarget.2890
Wagner J, Kline CL, Ralff MD, Lev A, Lulla A, Zhou L, et al. Preclinical evaluation of the imipridone family, analogues of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212. Cell Cycle. 2017;16:1790–9. https://doi.org/10.1080/15384101.2017.1325046
Juo P, Woo MSA, Kuo CJ, Signorelli P, Biemann HP, Hannun YA, et al. FADD is required for multiple signaling events downstream of the receptor Fas. Cell Growth Differ. 1999;10:797–804.
Sakuma T, Nakade S, Sakane Y, Suzuki KT, Yamamoto T. MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems. Nat Protoc. 2016;11:118–33. https://doi.org/10.1038/nprot.2015.140
Kojima K, Konopleva M, Tsao T, Andreeff M, Ishida H, Shiotsu Y, et al. Selective FLT3 inhibitor FI-700 neutralizes Mcl-1 and enhances p53-mediated apoptosis in AML cells with activating mutations of FLT3 through Mcl-1/Noxa axis. Leukemia. 2010;24:33–43. https://doi.org/10.1038/leu.2009.212
Chou TC, Motzer RJ, Tong Y, Bosl GJ. Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 1994;86:1517–24.
Chou TC. Preclinical versus clinical drug combination studies. Leuk Lymphoma. 2008;49:2059–80. https://doi.org/10.1080/10428190802353591
Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, et al. Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen. 2013;18:599–609. https://doi.org/10.1177/1087057113475480
Justus CR, Dong L, Yang LV. Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Front Physiol. 2013;4:354. https://doi.org/10.3389/fphys.2013.00354
Weng Z, Fluckiger AC, Nisitani S, Wahl MI, Le LQ, Hunter CA, et al. DNA damage and stress inducible G protein-coupled receptor blocks cells in G2/M. Proc Natl Acad Sci USA. 1998;95:12334–9. https://doi.org/10.1073/pnas.95.21.12334
Le LQ, Kabarowski JH, Wong S, Nguyen K, Gambhir SS, Witte ON. Positron emission tomography imaging analysis of G2A as a negative modifier of lymphoid leukemogenesis initiated by the BCR-ABL oncogene. Cancer Cell. 2002;1:381–91.
Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102. https://doi.org/10.1093/nar/gkx247
Lin P, Ye RD. The lysophospholipid receptor G2A activates a specific combination of G proteins and promotes apoptosis. J Biol Chem. 2003;278:14379–86. https://doi.org/10.1074/jbc.M209101200
Verma R, Rigatti MJ, Belinsky GS, Godman CA, Giardina C. DNA damage response to the Mdm2 inhibitor nutlin-3. Biochem Pharmacol. 2010;79:565–74. https://doi.org/10.1016/j.bcp.2009.09.020
Lev A, Lulla AR, Wagner J, Ralff MD, Kiehl JB, Zhou Y, et al. Anti-pancreatic cancer activity of ONC212 involves the unfolded protein response (UPR) and is reduced by IGF1-R and GRP78/BIP. Oncotarget. 2017;8:81776–93. https://doi.org/10.18632/oncotarget.20819
Akl H, Vervloessem T, Kiviluoto S, Bittremieux M, Parys JB, De Smedt H, et al. A dual role for the anti-apoptotic Bcl-2 protein in cancer: mitochondria versus endoplasmic reticulum. Biochim Biophys Acta. 2014;1843:2240–52. https://doi.org/10.1016/j.bbamcr.2014.04.017
Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8:705–11.
Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833:3460–70. https://doi.org/10.1016/j.bbamcr.2013.06.028
Kornblau SM, Thall PF, Estrov Z, Walterscheid M, Patel S, Theriault A, et al. The prognostic impact of BCL2 protein expression in acute myelogenous leukemia varies with cytogenetics. Clin Cancer Res. 1999;5:1758–66.
Ishizawa J, Kojima K, McQueen T, Ruvolo V, Chachad D, Nogueras-Gonzalez GM, et al. Mitochondrial profiling of acute myeloid leukemia in the assessment of response to apoptosis modulating drugs. PLoS One. 2015;10:e0138377 https://doi.org/10.1371/journal.pone.0138377
Cory S, Adams JM. The BCL2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2002;2:647–56. https://doi.org/10.1038/nrc883
Pan R, Hogdal LJ, Benito JM, Bucci D, Han L, Borthakur G, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4:362–75. https://doi.org/10.1158/2159-8290.cd-13-0609
Konopleva M, Pollyea DA, Potluri J, Chyla B, Hogdal L, Busman T, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6:1106–17. https://doi.org/10.1158/2159-8290.cd-16-0313
DiNardo C, Pollyea D, Pratz K, Thirman MJ, Letai A, Frattini M, et al. A phase 1b study of venetoclax (ABT-199/GDC-0199) in combination with decitabine or azacitidine in treatment-naive patients with acute myelogenous leukemia who are ≥ to 65 years and not eligible for standard induction therapy. Blood. 2015;126:327.
Pollyea DA, Stevens BM, Jones CL, Winters A, Pei S, Minhajuddin M, et al. Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia. Nat Med. 2018;24:1859–66. https://doi.org/10.1038/s41591-018-0233-1
Pollyea DA, Jordan CT. Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective? Curr Opin Hematol. 2019;26:71–6. https://doi.org/10.1097/moh.0000000000000485
Nakada D. Venetolax with azacitidine drains fuel from AML stem cells. Cell Stem Cell. 2019;24:7–8. https://doi.org/10.1016/j.stem.2018.12.005
Grundy M, Balakrishnan S, Fox M, Seedhouse CH, Russell NH. Genetic biomarkers predict response to dual BCL-2 and MCL-1 targeting in acute myeloid leukaemia cells. Oncotarget. 2018;9:37777–89. https://doi.org/10.18632/oncotarget.26540
Bate-Eya LT, den Hartog IJ, van der Ploeg I, Schild L, Koster J, Santo EE, et al. High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition. Oncotarget. 2016;7:27946–58. https://doi.org/10.18632/oncotarget.8547
Liu T, Wan Y, Liu R, Ma L, Li M, Fang H. Design, synthesis and preliminary biological evaluation of indole-3-carboxylic acid-based skeleton of Bcl-2/Mcl-1 dual inhibitors. Bioorg Med Chem. 2017;25:1939–48. https://doi.org/10.1016/j.bmc.2017.02.014
Pan R, Ruvolo V, Mu H, Leverson JD, Nichols G, Reed JC, et al. Synthetic lethality of combined Bcl-2 inhibition and p53 activation in AML: mechanisms and superior antileukemic efficacy. Cancer Cell. 2017;32:748–60. e6. https://doi.org/10.1016/j.ccell.2017.11.003
Daver N, Pollyea DA, Yee KWL, Fenaux P, Brandwein JM, Vey N, et al. Preliminary results from a phase ib study evaluating BCL-2 inhibitor venetoclax in combination with MEK inhibitor cobimetinib or MDM2 inhibitor idasanutlin in patients with relapsed or refractory (R/R) AML. Blood. 2017;130:813.
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).
Author information
Authors and Affiliations
Contributions
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.
Corresponding authors
Ethics declarations
Conflict of interest
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.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-019-0491-z
This article is cited by
-
FFAR4 activation inhibits lung adenocarcinoma via blocking respiratory chain complex assembly associated mitochondrial metabolism
Cellular & Molecular Biology Letters (2024)
-
ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia
Nature Communications (2023)
-
Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair
Nature Metabolism (2023)
-
Combined Drug Targeting of p53-dependent and -independent Pathways Depletes Myelofibrosis Hematopoietic Stem/Progenitor Cells
Leukemia (2022)
-
Inhibition of translation initiation factor eIF4a inactivates heat shock factor 1 (HSF1) and exerts anti-leukemia activity in AML
Leukemia (2021)