NT157, an IGF1R-IRS1/2 inhibitor, exhibits antineoplastic effects in pre-clinical models of chronic myeloid leukemia.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Disease Models, Animal
Drug Resistance, Neoplasm
/ drug effects
Fusion Proteins, bcr-abl
/ antagonists & inhibitors
Gene Expression Regulation, Neoplastic
Humans
Imatinib Mesylate
/ pharmacology
Insulin Receptor Substrate Proteins
/ antagonists & inhibitors
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ drug therapy
Mice
Protein Kinase Inhibitors
/ pharmacology
Pyrogallol
/ analogs & derivatives
Receptor, IGF Type 1
/ antagonists & inhibitors
Sulfonamides
/ pharmacology
BCR-ABL1
Insulin receptor substrate 1
Leukemogenesis
NT157
Journal
Investigational new drugs
ISSN: 1573-0646
Titre abrégé: Invest New Drugs
Pays: United States
ID NLM: 8309330
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
24
08
2020
accepted:
26
10
2020
pubmed:
7
1
2021
medline:
15
2
2022
entrez:
6
1
2021
Statut:
ppublish
Résumé
Chronic myeloid leukemia (CML) is successfully treated with BCR-ABL1 tyrosine kinase inhibitors, but a significant percentage of patients develop resistance. Insulin receptor substrate 1 (IRS1) has been shown to constitutively associate with BCR-ABL1, and IRS1-specific silencing leads to antineoplastic effects in CML cell lines. Here, we characterized the efficacy of NT157, a pharmacological inhibitor of IGF1R-IRS1/2, in CML cells and observed significantly reduced cell viability and proliferation, accompanied by induction of apoptosis. In human K562 cells and in murine Ba/F3 cells, engineered to express either wild-type BCR-ABL1 or the imatinib-resistant BCR-ABL1
Identifiants
pubmed: 33403501
doi: 10.1007/s10637-020-01028-8
pii: 10.1007/s10637-020-01028-8
doi:
Substances chimiques
Antineoplastic Agents
0
Insulin Receptor Substrate Proteins
0
NT157 compound
0
Protein Kinase Inhibitors
0
Sulfonamides
0
Pyrogallol
01Y4A2QXY0
Imatinib Mesylate
8A1O1M485B
Receptor, IGF Type 1
EC 2.7.10.1
Fusion Proteins, bcr-abl
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
736-746Références
Deininger MW, Goldman JM, Melo JV (2000) The molecular biology of chronic myeloid leukemia. Blood 96:3343–3356
doi: 10.1182/blood.V96.10.3343
O’Hare T, Eide CA, Deininger MW (2007) Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood 110:2242–2249
doi: 10.1182/blood-2007-03-066936
Hughes TP, Saglio G, Quintas-Cardama A, Mauro MJ, Kim DW, Lipton JH, Bradley-Garelik MB, Ukropec J, Hochhaus A (2015) BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase. Leukemia 29:1832–1838
doi: 10.1038/leu.2015.168
Apperley JF (2015) Chronic myeloid leukaemia. Lancet 385:1447–1459
doi: 10.1016/S0140-6736(13)62120-0
Wang LM, Myers MG Jr, Sun XJ, Aaronson SA, White M, Pierce JH (1993) IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells. Science 261:1591–1594
doi: 10.1126/science.8372354
Folli F, Saad MJ, Backer JM, Kahn CR (1992) Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat. J Biol Chem 267:22171–22177
doi: 10.1016/S0021-9258(18)41650-X
Skolnik EY, Batzer A, Li N, Lee CH, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J (1993) The function of GRB2 in linking the insulin receptor to Ras signaling pathways. Science 260:1953–1955
doi: 10.1126/science.8316835
Traina F, Carvalheira JB, Saad MJ, Costa FF, Saad ST (2003) BCR-ABL binds to IRS-1 and IRS-1 phosphorylation is inhibited by imatinib in K562 cells. FEBS Lett 535:17–22
doi: 10.1016/S0014-5793(02)03845-0
Machado-Neto JA, Favaro P, Lazarini M, Costa FF, Olalla Saad ST, Traina F (2011) Knockdown of insulin receptor substrate 1 reduces proliferation and downregulates Akt/mTOR and MAPK pathways in K562 cells. Biochim Biophys Acta 1813:1404–1411
doi: 10.1016/j.bbamcr.2011.04.002
Reuveni H, Flashner-Abramson E, Steiner L, Makedonski K, Song R, Shir A, Herlyn M, Bar-Eli M, Levitzki A (2013) Therapeutic destruction of insulin receptor substrates for cancer treatment. Cancer Res 73:4383–4394
doi: 10.1158/0008-5472.CAN-12-3385
Ibuki N, Ghaffari M, Reuveni H, Pandey M, Fazli L, Azuma H, Gleave ME, Levitzki A, Cox ME (2014) The tyrphostin NT157 suppresses insulin receptor substrates and augments therapeutic response of prostate cancer. Mol Cancer Ther 13:2827–2839
doi: 10.1158/1535-7163.MCT-13-0842
Garofalo C, Capristo M, Mancarella C, Reunevi H, Picci P, Scotlandi K (2015) Preclinical effectiveness of selective inhibitor of IRS-1/2 NT157 in osteosarcoma cell lines. Front Endocrinol (Lausanne) 6:74
doi: 10.3389/fendo.2015.00074
Flashner-Abramson E, Klein S, Mullin G, Shoshan E, Song R, Shir A, Langut Y, Bar-Eli M, Reuveni H, Levitzki A (2016) Targeting melanoma with NT157 by blocking Stat3 and IGF1R signaling. Oncogene 35:2675–2680
doi: 10.1038/onc.2015.229
Sanchez-Lopez E, Flashner-Abramson E, Shalapour S, Zhong Z, Taniguchi K, Levitzki A, Karin M (2016) Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and STAT3 signaling. Oncogene 35:2634–2644
doi: 10.1038/onc.2015.326
Yang Y, Chan JY, Temiz NA, Yee D (2018) Insulin receptor substrate suppression by the tyrphostin NT157 inhibits responses to insulin-like growth factor-I and insulin in breast cancer cells. Horm Cancer 9(6):371–382
doi: 10.1007/s12672-018-0343-8
Vardiman JW, Melo JV, Baccarani M, Radich JP, Kvasnicka HM (2017) Chronic myeloid leukaemi, BCR-ABL1-positive. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (eds) WHO classification of tumors of haematopoietic and lymphoid tissues. IARC, Lyon, pp 30–36
Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681
doi: 10.1124/pr.58.3.10
Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M, Pirritt C, Sun Y, Yao Y, Arnold LD, Gibson NW, Ji QS (2009) Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem 1:1153–1171
doi: 10.4155/fmc.09.89
Juric D, Lacayo NJ, Ramsey MC, Racevskis J, Wiernik PH, Rowe JM, Goldstone AH, O’Dwyer PJ, Paietta E, Sikic BI (2007) Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias. J Clin Oncol 25:1341–1349
doi: 10.1200/JCO.2006.09.3534
Fenerich BA, Fernandes JC, Rodrigues Alves APN, Coelho-Silva JL, Scopim-Ribeiro R, Scheucher PS, Eide CA, Tognon CE, Druker BJ, Rego EM, Machado-Neto JA, Traina F (2020) NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells. Signal Transduction Target Ther 5:5
doi: 10.1038/s41392-019-0102-5
Lakshmikuttyamma A, Pastural E, Takahashi N, Sawada K, Sheridan DP, DeCoteau JF, Geyer CR (2008) Bcr-Abl induces autocrine IGF-1 signaling. Oncogene 27:3831–3844
doi: 10.1038/onc.2008.8
Xie J, Chen X, Zheng J, Li C, Stacy S, Holzenberger M, Hu X, Zhang CC (2015) IGF-IR determines the fates of BCR/ABL leukemia. J Hematol Oncol 8:3
doi: 10.1186/s13045-015-0106-8
Abraham SA, Hopcroft LE, Carrick E, Drotar ME, Dunn K, Williamson AJ, Korfi K, Baquero P, Park LE, Scott MT, Pellicano F, Pierce A, Copland M, Nourse C, Grimmond SM, Vetrie D, Whetton AD, Holyoake TL (2016) Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. Nature 534:341–346
doi: 10.1038/nature18288
Carter BZ, Mak PY, Mu H, Zhou H, Mak DH, Schober W, Leverson JD, Zhang B, Bhatia R, Huang X, Cortes J, Kantarjian H, Konopleva M, Andreeff M (2016) Combined targeting of BCL-2 and BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia stem cells. Sci Transl Med 8:355ra117
doi: 10.1126/scitranslmed.aag1180
Passegue E, Wagner EF, Weissman IL (2004) JunB deficiency leads to a myeloproliferative disorder arising from hematopoietic stem cells. Cell 119:431–443
doi: 10.1016/j.cell.2004.10.010
Yang MY, Liu TC, Chang JG, Lin PM, Lin SF (2003) JunB gene expression is inactivated by methylation in chronic myeloid leukemia. Blood 101:3205–3211
doi: 10.1182/blood-2002-05-1598
Hoshino K, Quintas-Cardama A, Radich J, Dai H, Yang H, Garcia-Manero G (2009) Downregulation of JUNB mRNA expression in advanced phase chronic myelogenous leukemia. Leuk Res 33:1361–1366
doi: 10.1016/j.leukres.2009.03.044
O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, Adrian LT, Zhou T, Huang WS, Xu Q, Metcalf CA III, Tyner JW, Loriaux MM, Corbin AS, Wardwell S, Ning Y, Keats JA, Wang Y, Sundaramoorthi R, Thomas M, Zhou D, Snodgrass J, Commodore L, Sawyer TK, Dalgarno DC, Deininger MW, Druker BJ, Clackson T (2009) AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16:401–412
doi: 10.1016/j.ccr.2009.09.028
Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O’Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M (2012) Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med 367:2075–2088
doi: 10.1056/NEJMoa1205127
Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Muller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H (2013) A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med 369:1783–1796
doi: 10.1056/NEJMoa1306494
Moslehi JJ, Deininger M (2015) Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol 33:4210–4218
doi: 10.1200/JCO.2015.62.4718