Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
06
02
2019
accepted:
17
04
2019
revised:
30
03
2019
pubmed:
7
6
2019
medline:
1
7
2020
entrez:
8
6
2019
Statut:
ppublish
Résumé
MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.
Identifiants
pubmed: 31171817
doi: 10.1038/s41375-019-0503-z
pii: 10.1038/s41375-019-0503-z
pmc: PMC6895415
mid: NIHMS1527348
doi:
Substances chimiques
Antineoplastic Agents, Phytogenic
0
Plant Extracts
0
Proto-Oncogene Proteins c-myc
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
138-150Subventions
Organisme : NCI NIH HHS
ID : P30 CA036727
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM111625
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM118173
Pays : United States
Références
Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood. 2013;122:3884–91.
pubmed: 24009228
Sabo A, Kress TR, Pelizzola M, de Pretis S, Gorski MM, Tesi A, et al. Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis. Nature. 2014;511:488–92.
pubmed: 25043028
pmcid: 4110711
Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151:68–79.
pubmed: 23021216
pmcid: 3471363
Scott DW, King RL, Staiger AM, Ben-Neriah S, Jiang A, Horn H, et al. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology. Blood. 2018;131:2060–4.
pubmed: 29475959
pmcid: 6158813
Savage KJ, Johnson NA, Ben-Neriah S, Connors JM, Sehn LH, Farinha P, et al. MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood. 2009;114:3533–7.
pubmed: 19704118
Barrans S, Crouch S, Smith A, Turner K, Owen R, Patmore R, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28:3360–5.
pubmed: 20498406
Aukema SM, Siebert R, Schuuring E, van Imhoff GW, Kluin-Nelemans HC, Boerma EJ, et al. Double-hit B-cell lymphomas. Blood. 2011;117:2319–31.
pubmed: 21119107
Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375–90.
pubmed: 26980727
pmcid: 4874220
Sarkozy C, Traverse-Glehen A, Coiffier B. Double-hit and double-protein-expression lymphomas: aggressive and refractory lymphomas. Lancet Oncol. 2015;16:e555–e67.
pubmed: 26545844
Johnson NA, Savage KJ, Ludkovski O, Ben-Neriah S, Woods R, Steidl C, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood. 2009;114:2273–9.
pubmed: 19597184
pmcid: 2745846
Green TM, Young KH, Visco C, Xu-Monette ZY, Orazi A, Go RS, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2012;30:3460–7.
pubmed: 22665537
Doroshow DB, Eder JP, LoRusso PM. BET inhibitors: a novel epigenetic approach. Ann Oncol. 2017;28:1776–87.
pubmed: 28838216
Stathis A, Zucca E, Bekradda M, Gomez-Roca C, Delord JP, de La Motte Rouge T, et al. Clinical response of carcinomas harboring the BRD4-NUT oncoprotein to the targeted bromodomain inhibitor OTX015/MK-8628. Cancer Discov. 2016;6:492–500.
pubmed: 26976114
pmcid: 4854801
Pawar A, Gollavilli PN, Wang S, Asangani IA. Resistance to BET inhibitor leads to alternative therapeutic vulnerabilities in castration-resistant prostate cancer. Cell Rep. 2018;22:2236–45.
pubmed: 29490263
Kurimchak AM, Shelton C, Duncan KE, Johnson KJ, Brown J, O’Brien S, et al. Resistance to BET bromodomain inhibitors is mediated by kinome reprogramming in ovarian cancer. Cell Rep. 2016;16:1273–86.
pubmed: 27452461
pmcid: 4972668
Barna M, Pusic A, Zollo O, Costa M, Kondrashov N, Rego E, et al. Suppression of Myc oncogenic activity by ribosomal protein haploinsufficiency. Nature. 2008;456:971–5.
pubmed: 19011615
pmcid: 2880952
Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14:261–78.
pubmed: 25743081
Hinnebusch AG, Ivanov IP, Sonenberg N. Translational control by 5’-untranslated regions of eukaryotic mRNAs. Science. 2016;352:1413–6.
pubmed: 27313038
Topisirovic I, Svitkin YV, Sonenberg N, Shatkin AJ. Cap and cap-binding proteins in the control of gene expression. Wiley Inter Rev Rna. 2011;2:277–98.
Ravitz MJ, Chen L, Lynch M, Schmidt EV. c-myc repression of TSC2 contributes to control of translation initiation and Myc-induced transformation. Cancer Res. 2007;67:11209–17.
pubmed: 18056446
pmcid: 3022657
Elkon R, Loayza-Puch F, Korkmaz G, Lopes R, van Breugel PC, Bleijerveld OB, et al. Myc coordinates transcription and translation to enhance transformation and suppress invasiveness. EMBO Rep. 2015;16:1723–36.
pubmed: 26538417
pmcid: 4687422
Lucas DM, Edwards RB, Lozanski G, West DA, Shin JD, Vargo MA, et al. The novel plant-derived agent silvestrol has B-cell selective activity in chronic lymphocytic leukemia and acute lymphoblastic leukemia in vitro and in vivo. Blood. 2009;113:4656–66.
pubmed: 19190247
pmcid: 2680369
Manier S, Huynh D, Shen YJ, Zhou J, Yusufzai T, Salem KZ, et al. Inhibiting the oncogenic translation program is an effective therapeutic strategy in multiple myeloma. Sci Transl Med. 2017;9:389.
Pan L, Woodard JL, Lucas DM, Fuchs JR, Kinghorn AD. Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species. Nat Prod Rep. 2014;31:924–39.
pubmed: 24788392
pmcid: 4091845
Bordeleau ME, Robert F, Gerard B, Lindqvist L, Chen SM, Wendel HG, et al. Therapeutic suppression of translation initiation modulates chemosensitivity in a mouse lymphoma model. J Clin Invest. 2008;118:2651–60.
pubmed: 18551192
pmcid: 2423864
Wiegering A, Uthe FW, Jamieson T, Ruoss Y, Huttenrauch M, Kuspert M, et al. Targeting translation initiation bypasses signaling crosstalk mechanisms that maintain high MYC levels in colorectal cancer. Cancer Discov. 2015;5:768–81.
pubmed: 25934076
pmcid: 5166973
Robert F, Roman W, Bramoulle A, Fellmann C, Roulston A, Shustik C, et al. Translation initiation factor eIF4F modifies the dexamethasone response in multiple myeloma. Proc Natl Acad Sci USA. 2014;111:13421–6.
pubmed: 25197055
Rong L, Livingstone M, Sukarieh R, Petroulakis E, Gingras AC, Crosby K, et al. Control of eIF4E cellular localization by eIF4E-binding proteins, 4E-BPs. RNA. 2008;14:1318–27.
pubmed: 18515545
pmcid: 2441981
Pettersson F, Del Rincon SV, Miller WH Jr.. Eukaryotic translation initiation factor 4E as a novel therapeutic target in hematological malignancies and beyond. Expert Opin Ther Targets. 2014;18:1035–48.
pubmed: 25004955
Yang T, Buchan HL, Townsend KJ, Craig RWMCL-1. a member of the BLC-2 family, is induced rapidly in response to signals for cell differentiation or death, but not to signals for cell proliferation. J Cell Physiol. 1996;166:523–36.
pubmed: 8600156
Raynaud FI, Orr RM, Goddard PM, Lacey HA, Lancashire H, Judson IR, et al. Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J Pharm Exp Ther. 1997;281:420–7.
Pestova TV, Shatsky IN, Hellen CU. Functional dissection of eukaryotic initiation factor 4F: the 4A subunit and the central domain of the 4G subunit are sufficient to mediate internal entry of 43S preinitiation complexes. Mol Cell Biol. 1996;16:6870–8.
pubmed: 8943342
pmcid: 231690
Svitkin YV, Pause A, Haghighat A, Pyronnet S, Witherell G, Belsham GJ, et al. The requirement for eukaryotic initiation factor 4A (elF4A) in translation is in direct proportion to the degree of mRNA 5’ secondary structure. RNA. 2001;7:382–94.
pubmed: 11333019
pmcid: 1370095
Chu J, Galicia-Vazquez G, Cencic R, Mills JR, Katigbak A, Porco JA Jr., et al. CRISPR-mediated drug-target validation reveals selective pharmacological inhibition of the RNA helicase, eIF4A. Cell Rep. 2016;15:2340–7.
pubmed: 27239032
pmcid: 5315212
Pelletier J, Graff J, Ruggero D, Sonenberg N. Targeting the eIF4F translation initiation complex: a critical nexus for cancer development. Cancer Res. 2015;75:250–63.
pubmed: 25593033
pmcid: 4299928
Iwasaki S, Iwasaki W, Takahashi M, Sakamoto A, Watanabe C, Shichino Y, et al. The Translation inhibitor rocaglamide targets a bimolecular cavity between eIF4A and polypurine RNA. Mol Cell. 2019;73:P738–748.E9.
pubmed: 30595437
Iwasaki S, Floor SN, Ingolia NT. Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor. Nature. 2016;534:558–61.
pubmed: 27309803
pmcid: 4946961
Chambers JM, Lindqvist LM, Webb A, Huang DC, Savage GP, Rizzacasa MA. Synthesis of biotinylated episilvestrol: highly selective targeting of the translation factors eIF4AI/II. Org Lett. 2013;15:1406–9.
pubmed: 23461621
Andreou AZ, Klostermeier D. The DEAD-box helicase eIF4A: paradigm or the odd one out? RNA Biol. 2013;10:19–32.
pubmed: 22995829
pmcid: 3590233
Oblinger JL, Burns SS, Akhmametyeva EM, Huang J, Pan L, Ren Y, et al. Components of the eIF4F complex are potential therapeutic targets for malignant peripheral nerve sheath tumors and vestibular schwannomas. Neuro Oncol. 2016;18:1265–77.
pubmed: 26951381
pmcid: 4998994
Galicia-Vazquez G, Cencic R, Robert F, Agenor AQ, Pelletier J. A cellular response linking eIF4AI activity to eIF4AII transcription. RNA. 2012;18:1373–84.
pubmed: 22589333
pmcid: 3383968
Chu J, Cencic R, Wang W, Porco JA Jr., Pelletier J. Translation inhibition by rocaglates is independent of eIF4E phosphorylation status. Mol cancer Ther. 2016;15:136–41.
pubmed: 26586722
den Hollander J, Rimpi S, Doherty JR, Rudelius M, Buck A, Hoellein A, et al. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood. 2010;116:1498–505.
Ren Y, Bi C, Zhao X, Lwin T, Wang C, Yuan J, et al. PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest. 2018;128:5517–30.
pubmed: 30260324
pmcid: 6264635
Malka-Mahieu H, Newman M, Desaubry L, Robert C, Vagner S. Molecular pathways: the eIF4F translation initiation complex-new opportunities for cancer treatment. Clin Cancer Res. 2017;23:21–5.
pubmed: 27789529
Lin CJ, Malina A, Pelletier J. c-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. Cancer Res. 2009;69:7491–4.
pubmed: 19773439
Cope CL, Gilley R, Balmanno K, Sale MJ, Howarth KD, Hampson M, et al. Adaptation to mTOR kinase inhibitors by amplification of eIF4E to maintain cap-dependent translation. J Cell Sci. 2014;127(Pt 4):788–800.
pubmed: 24363449
Duncan R, Hershey JW. Identification and quantitation of levels of protein synthesis initiation factors in crude HeLa cell lysates by two-dimensional polyacrylamide gel electrophoresis. J Biol Chem. 1983;258:7228–35.
pubmed: 6853516
Peters TL, Tillotson J, Yeomans AM, Wilmore S, Lemm E, Jimenez-Romero C, et al. Target-based screening against eIF4A1 reveals the marine natural product elatol as a novel inhibitor of translation initiation with in vivo antitumor activity. Clin Cancer Res. 2018;24:4256–70.
pubmed: 29844128
pmcid: 6500731
Cencic R, Pelletier J. Hippuristanol - a potent steroid inhibitor of eukaryotic initiation factor 4A. Transl (Austin). 2016;4:e1137381.
Bonetti P, Testoni M, Scandurra M, Ponzoni M, Piva R, Mensah AA, et al. Deregulation of ETS1 and FLI1 contributes to the pathogenesis of diffuse large B-cell lymphoma. Blood. 2013;122:2233–41.
pubmed: 23926301
Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med. 2014;4. pii: a014282.
Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: switching an oncogene to a tumor suppressor. Blood. 2014;123:2451–9.
pubmed: 24608975
pmcid: 3990910
Basso K, Dalla-Favera R. BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis. Adv Immunol. 2010;105:193–210.
pubmed: 20510734
Bi C, Zhang X, Lu T, Zhang X, Wang X, Meng B, et al. Inhibition of 4EBP phosphorylation mediates the cytotoxic effect of mechanistic target of rapamycin kinase inhibitors in aggressive B-cell lymphomas. Haematologica. 2017;102:755–64.
pubmed: 28104700
pmcid: 5395116
Yueh H, Gao Q, Porco JA Jr., Beeler AB. A photochemical flow reactor for large scale syntheses of aglain and rocaglate natural product analogues. Bioorg Med Chem. 2017;25:6197–202.
pubmed: 28666859
pmcid: 5696104
Stone SD, Lajkiewicz NJ, Whitesell L, Hilmy A, Porco JA Jr. Biomimetic kinetic resolution: highly enantio- and diastereoselective transfer hydrogenation of aglain ketones to access flavagline natural products. J Am Chem Soc. 2015;137:525–30.
pubmed: 25514979
Rodrigo CM, Cencic R, Roche SP, Pelletier J, Porco JA. Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: synthetic and biological studies. J Med Chem. 2012;55:558–62.
pubmed: 22128783
Wang W, Cencic R, Whitesell L, Pelletier J, Porco JA Jr. Synthesis of Aza-rocaglates via ESIPT-mediated (3+2) photocycloaddition. Chemistry. 2016;22:12006–10.
pubmed: 27338157
pmcid: 5224829
Saradhi UV, Gupta SV, Chiu M, Wang J, Ling Y, Liu Z, et al. Characterization of silvestrol pharmacokinetics in mice using liquid chromatography-tandem mass spectrometry. AAPS J. 2011;13:347–56.
pubmed: 21499689
pmcid: 3160157