2,230
Views
28
CrossRef citations to date
0
Altmetric
Review

Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

, , , &
Pages 648-656 | Received 24 Feb 2015, Accepted 01 Mar 2015, Published online: 21 May 2015

References

  • Gentzler RD, Altman JK, Platanias LC. An overview of the mTOR pathway as a target in cancer therapy. Expert Opin Ther Targets 2012; 16:481–9; PMID:22494490; http://dx.doi.org/10.1517/14728222.2012.677439
  • Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27:5497–510; PMID:18794884; http://dx.doi.org/10.1038/onc.2008.245
  • Porta C, Paglino C, Mosca A. Targeting PI3K/AKT/mTOR Signaling in Cancer. Front Oncol 2014; 4:64; PMID:24782981; http://dx.doi.org/10.3389/fonc.2014.00064
  • Kwitkowski VE, Prowell TM, Ibrahim A, Farrell AT, Justice R, Mitchell SS, Sridhara R, Pazdur R. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 2010; 15:428–35; PMID:20332142; http://dx.doi.org/10.1634/theoncologist.2009-0178
  • Lebwohl D, Anak O, Sahmoud T, Klimovsky J, Elmroth I, Haas T, Posluszny J, Saletan S, Berg W. Development of everolimus, a novel oral mTOR inhibitor, across a spectrum of diseases. Ann N Y Acad Sci 2013; 1291:14–32; PMID:23659703; http://dx.doi.org/10.1111/nyas.12122
  • Markham A. Idelalisib: first global approval. Drugs 2014; 74:1701–7; PMID:25187123; http://dx.doi.org/10.1007/s40265-014-0285-6
  • Altman JK, Platanias LC. Acute myeloid leukemia: potential for new therapeutic approaches targeting mRNA translation pathways. Int J Hematol Oncol 2013; 2:10.2217/ijh.13.23; PMID:24319589; http://dx.doi.org/10.2217/ijh.13.23
  • Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Manzoli L, McCubrey JA. Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opin Investig Drugs 2009; 18:1333–49; PMID:19678801; http://dx.doi.org/10.1517/14728220903136775
  • Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, Lee ST, Lee MH, Hahn JS, Ko YW. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia 2003; 17:995–7; PMID:12750723; http://dx.doi.org/10.1038/sj.leu.2402874
  • Bertacchini J, Guida M, Accordi B, Mediani L, Martelli AM, Barozzi P, Petricoin E, 3rd, Liotta L, Milani G, Giordan M, et al. Feedbacks and adaptive capabilities of the PI3K/AKT/mTOR axis in acute myeloid leukemia revealed by pathway selective inhibition and phosphoproteome analysis. Leukemia 2014; 28:2197–205; PMID:24699302; http://dx.doi.org/10.1038/leu.2014.123
  • Zeng Z, Shi YX, Tsao T, Qiu Y, Kornblau SM, Baggerly KA, Liu W, Jessen K, Liu Y, Kantarjian H, et al. Targeting of mTORC1/2 by the mTOR kinase inhibitor PP242 induces apoptosis in AML cells under conditions mimicking the bone marrow microenvironment. Blood 2012; 120:2679–89; PMID:22826565; http://dx.doi.org/10.1182/blood-2011-11-393934
  • Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003; 102:972–80; PMID:12702506; http://dx.doi.org/10.1182/blood-2002-11-3429
  • Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM, Benzaquen D, Laurent G, Huguet F, Payrastre B. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005; 105:2527–34; PMID:15550488; http://dx.doi.org/10.1182/blood-2004-06-2494
  • Martelli AM, Tazzari PL, Evangelisti C, Chiarini F, Blalock WL, Billi AM, Manzoli L, McCubrey JA, Cocco L. Targeting the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin module for acute myelogenous leukemia therapy: from bench to bedside. Curr Med Chem 2007; 14:2009–23; PMID:17691943; http://dx.doi.org/10.2174/092986707781368423
  • Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001–2007. Blood 2012; 119:34–43; PMID:22086414; http://dx.doi.org/10.1182/blood-2011-04-347872
  • Valent P. Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept. Curr Cancer Drug Targets 2011; 11:56–71; PMID:21062243; http://dx.doi.org/10.2174/156800911793743655
  • Zeijlemaker W, Gratama JW, Schuurhuis GJ. Tumor heterogeneity makes AML a “moving target” for detection of residual disease. Cytometry B Clin Cytom 2014; 86:3–14; PMID:24151248; http://dx.doi.org/10.1002/cyto.b.21134
  • Shah A, Andersson TM, Rachet B, Bjorkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971–2006: a population-based study. Br J Haematol 2013; 162:509–16; PMID:23786647; http://dx.doi.org/10.1111/bjh.12425
  • Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley K, Harrison CJ, Burnett AK. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 116:354–65; PMID:20385793; http://dx.doi.org/10.1182/blood-2009-11-254441
  • Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, Van Vlierberghe P, Dolgalev I, Thomas S, Aminova O, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012; 366:1079–89; PMID:22417203; http://dx.doi.org/10.1056/NEJMoa1112304
  • Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N, et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 2005; 106:1063–6; PMID:15840695; http://dx.doi.org/10.1182/blood-2004-08-3225
  • Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B, Khwaja A. A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16. Oncogene 2006; 25:6648–59; PMID:16702948; http://dx.doi.org/10.1038/sj.onc.1209670
  • Altman JK, Sassano A, Platanias LC. Targeting mTOR for the treatment of AML. New agents and new directions. Oncotarget 2011; 2:510–7; PMID:21680954
  • Sanja P, Ivo U, Boris L, Damir N, Josip B, Renata Z, Suncica R, Koraljka GK, Sanja D, Drago B. Prognostic significance of constitutive PI3K/Akt and MAPK phosphorylation in acute myeloid leukemia. Leuk Lymphoma 2014; published on line December 29 2014, http://dx.doi.org/10.3109/10428194.2014.990012
  • Jucker M, Sudel K, Horn S, Sickel M, Wegner W, Fiedler W, Feldman RA. Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO). Leukemia 2002; 16:894–901; PMID:11986952; http://dx.doi.org/10.1038/sj.leu.2402484
  • Muller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT, Koeffler HP. Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res 2007; 31:27–32; PMID:16764926; http://dx.doi.org/10.1016/j.leukres.2006.04.011
  • Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood 2012; 120:3397–406; PMID:22898602; http://dx.doi.org/10.1182/blood-2012-05-378596
  • Johnson DB, Smalley KS, Sosman JA. Molecular pathways: targeting NRAS in melanoma and acute myelogenous leukemia. Clin Cancer Res 2014; 20:4186–92; PMID:24895460; http://dx.doi.org/10.1158/1078-0432.CCR-13-3270
  • Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer 2011; 11:761–74; PMID:21993244; http://dx.doi.org/10.1038/nrc3106
  • Lonetti A, Antunes IL, Chiarini F, Orsini E, Buontempo F, Ricci F, Tazzari PL, Pagliaro P, Melchionda F, Pession A, et al. Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia 2014; 28:1196–206; PMID:24310736; http://dx.doi.org/10.1038/leu.2013.369
  • Nguyen LX, Sesay A, Mitchell BS. Effect of CAL-101, a PI3Kdelta inhibitor, on ribosomal rna synthesis and cell proliferation in acute myeloid leukemia cells. Blood Cancer J 2014; 4:e228; PMID:25014775; http://dx.doi.org/10.1038/bcj.2014.49
  • Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C, Maira SM, Hollingworth G, Choi C, Khandan T, et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. J Clin Invest 2014; 124:1794–809; PMID:24569456; http://dx.doi.org/10.1172/JCI69927
  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307:1098–101; PMID:15718470; http://dx.doi.org/10.1126/science.1106148
  • Sandhofer N, Metzeler KH, Rothenberg M, Herold T, Tiedt S, Groiss V, Carlet M, Walter G, Hinrichsen T, Wachter O, et al. Dual PI3K/mTOR inhibition shows antileukemic activity in MLL-rearranged acute myeloid leukemia. Leukemia 2014; Oct 17; [Epub ahead of print]; PMID:25322685, http://dx.doi.org/10.1038/leu.2014.305
  • Castellano E, Downward J. Role of RAS in the regulation of PI 3-kinase. Curr Top Microbiol Immunol 2010; 346:143–69; PMID:20563706
  • Wunderle L, Badura S, Lang F, Wolf A, Schleyer E, Serve H, Goekbuget N, Pfeifer H, Bug G, Ottmann OG. Safety and Efficacy Of BEZ235, a Dual PI3-Kinase /mTOR Inhibitor, In Adult Patients With Relapsed Or Refractory Acute Leukemia: Results Of a Phase I Study. Blood 2013; 122: abstract 2675
  • Chen J, Shao R, Li L, Xu ZP, Gu W. Effective inhibition of colon cancer cell growth with MgAl-layered double hydroxide (LDH) loaded 5-FU and PI3K/mTOR dual inhibitor BEZ-235 through apoptotic pathways. Int J Nanomedicine 2014; 9:3403–11; PMID:25075187
  • Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, Falkenburg JH, Ruthardt M, Ottmann OG. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One 2013; 8:e80070; PMID:24244612; http://dx.doi.org/10.1371/journal.pone.0080070
  • Jabbour E, Ottmann OG, Deininger M, Hochhaus A. Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies. Haematologica 2014; 99:7–18; PMID:24425689; http://dx.doi.org/10.3324/haematol.2013.087171
  • Kampa-Schittenhelm KM, Heinrich MC, Akmut F, Rasp KH, Illing B, Dohner H, Dohner K, Schittenhelm MM. Cell cycle-dependent activity of the novel dual PI3K-MTORC1/2 inhibitor NVP-BGT226 in acute leukemia. Mol Cancer 2013; 12:46; PMID:23705826; http://dx.doi.org/10.1186/1476-4598-12-46
  • Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7:261–9; PMID:9094314; http://dx.doi.org/10.1016/S0960-9822(06)00122-9
  • Vanhaesebroeck B, Alessi DR. The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 2000; 346:561–76; PMID:10698680; http://dx.doi.org/10.1042/0264-6021:3460561
  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 1997; 91:231–41; PMID:9346240; http://dx.doi.org/10.1016/S0092-8674(00)80405-5
  • Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 1999; 401:86–90; PMID:10485711; http://dx.doi.org/10.1038/43474
  • Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998; 12:3499–511; PMID:9832503; http://dx.doi.org/10.1101/gad.12.22.3499
  • Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648–57; PMID:12172553; http://dx.doi.org/10.1038/ncb839
  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96:857–68; PMID:10102273; http://dx.doi.org/10.1016/S0092-8674(00)80595-4
  • Laplante M, Sabatini DM. Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 2013; 126:1713–19; PMID:23641065; http://dx.doi.org/10.1242/jcs.125773
  • Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, Buerger H, Muller-Tidow C, Choudhary C, McMahon M, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res 2005; 65:9643–50; PMID:16266983; http://dx.doi.org/10.1158/0008-5472.CAN-05-0422
  • Grandage VL, Gale RE, Linch DC, Khwaja A. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia 2005; 19:586–94; PMID:15703783
  • Gallay N, Dos Santos C, Cuzin L, Bousquet M, Simmonet Gouy V, Chaussade C, Attal M, Payrastre B, Demur C, Recher C. The level of AKT phosphorylation on threonine 308 but not on serine 473 is associated with high-risk cytogenetics and predicts poor overall survival in acute myeloid leukaemia. Leukemia 2009; 23:1029–38; PMID:19158829; http://dx.doi.org/10.1038/leu.2008.395
  • Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, Verstovsek S, Faderl S, Garcia-Manero G, List AF, et al. Phase I clinical, pharmacokinetic, and pharmacodynamic study of the Akt-inhibitor triciribine phosphate monohydrate in patients with advanced hematologic malignancies. Leuk Res 2013; 37:1461–67; PMID:23993427; http://dx.doi.org/10.1016/j.leukres.2013.07.034
  • Papa V, Tazzari PL, Chiarini F, Cappellini A, Ricci F, Billi AM, Evangelisti C, Ottaviani E, Martinelli G, Testoni N, et al. Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells. Leukemia 2008; 22:147–60; PMID:17928881; http://dx.doi.org/10.1038/sj.leu.2404980
  • Krawczyk J, Keane N, Swords R, O'Dwyer M, Freeman CL, Giles FJ. Perifosine–a new option in treatment of acute myeloid leukemia? Expert Opin Investig Drugs 2013; 22:1315–27; PMID:23931614; http://dx.doi.org/10.1517/13543784.2013.826648
  • Richardson PG, Nagler A, Ben-Yehuda D, Badros A, Hari P, Hajek R, Spicka I, Kaya H, Le Blanc R, Yoon S-S, et al. Randomized Placebo-Controlled Phase III Study Of Perifosine Combined With Bortezomib and Dexamethasone In Relapsed, Refractory Multiple Myeloma Patients Previously Treated With Bortezomib. Blood 2013; 122: abstract 3189; http://dx.doi.org/10.1182/blood-2013-01-481325
  • Figg WD, Monga M, Headlee D, Shah A, Chau CH, Peer C, Messman R, Elsayed YA, Murgo AJ, Melillo G, et al. A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms. Cancer Chemother Pharmacol 2014; 74:955–67; PMID:25183650; http://dx.doi.org/10.1007/s00280-014-2569-7
  • Gojo I, Perl A, Luger S, Baer MR, Norsworthy KJ, Bauer KS, Tidwell M, Fleckinger S, Carroll M, Sausville EA. Phase I study of UCN-01 and perifosine in patients with relapsed and refractory acute leukemias and high-risk myelodysplastic syndrome. Invest New Drugs 2013; 31:1217–27; PMID:23443507; http://dx.doi.org/10.1007/s10637-013-9937-8
  • Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder PK, Pan BS, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010; 9:1956–67; PMID:20571069; http://dx.doi.org/10.1158/1535-7163.MCT-09-1012
  • Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K, et al. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res 2008; 68:2366–74; PMID:18381444; http://dx.doi.org/10.1158/0008-5472.CAN-07-5783
  • Konopleva MY, Walter RB, Faderl SH, Jabbour EJ, Zeng Z, Borthakur G, Huang X, Kadia TM, Ruvolo PP, Feliu JB, et al. Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Clin Cancer Res 2014; 20:2226–35; PMID:24583795; http://dx.doi.org/10.1158/1078-0432.CCR-13-1978
  • Meng J, Dai B, Fang B, Bekele BN, Bornmann WG, Sun D, Peng Z, Herbst RS, Papadimitrakopoulou V, Minna JD, et al. Combination treatment with MEK and AKT inhibitors is more effective than each drug alone in human non-small cell lung cancer in vitro and in vivo. PLoS One 2010; 5:e14124; PMID:21124782; http://dx.doi.org/10.1371/journal.pone.0014124
  • Floc'h N, Kinkade CW, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A, Cardiff RD, Califano A, Shen MM, Abate-Shen C. Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res 2012; 72:4483–93; PMID:22815528; http://dx.doi.org/10.1158/0008-5472.CAN-12-0283
  • Sun D, Sawada A, Nakashima M, Kobayashi T, Ogawa O, Matsui Y. MK2206 potentiates cisplatin-induced cytotoxicity and apoptosis through an interaction of inactivated Akt signaling pathway. Urol Oncol 2014; S1078-1439(14)00363–9 published on line December 9 2014, http://dx.doi.org/10.1016/j.urolonc.2014.10.018
  • Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood 2009; 113:1723–29; PMID:19064730; http://dx.doi.org/10.1182/blood-2008-02-137737
  • Lucero-Acuna A, Jeffery JJ, Abril ER, Nagle RB, Guzman R, Pagel MD, Meuillet EJ. Nanoparticle delivery of an AKT/PDK1 inhibitor improves the therapeutic effect in pancreatic cancer. Int J Nanomedicine 2014; 9:5653–65; PMID:25516710
  • Pearce LR, Komander D, Alessi DR. The nuts and bolts of AGC protein kinases. Nat Rev Mol Cell Biol 2010; 11:9–22; PMID:20027184; http://dx.doi.org/10.1038/nrm2822
  • Flynn P, Wongdagger M, Zavar M, Dean NM, Stokoe D. Inhibition of PDK-1 activity causes a reduction in cell proliferation and survival. Curr Biol 2000; 10:1439–42; PMID:11102805; http://dx.doi.org/10.1016/S0960-9822(00)00801-0
  • Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY, et al. AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 2009; 16:21–32; PMID:19573809; http://dx.doi.org/10.1016/j.ccr.2009.04.012
  • Feldman RI, Wu JM, Polokoff MA, Kochanny MJ, Dinter H, Zhu D, Biroc SL, Alicke B, Bryant J, Yuan S, et al. Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem 2005; 280:19867–74; PMID:15772071; http://dx.doi.org/10.1074/jbc.M501367200
  • Peifer C, Alessi DR. Small-molecule inhibitors of PDK1. ChemMedChem 2008; 3:1810–38; PMID:18972468; http://dx.doi.org/10.1002/cmdc.200800195
  • Najafov A, Sommer EM, Axten JM, Deyoung MP, Alessi DR. Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1. Biochem J 2011; 433:357–69; PMID:21087210; http://dx.doi.org/10.1042/BJ20101732
  • Pearn L, Fisher J, Burnett AK, Darley RL. The role of PKC and PDK1 in monocyte lineage specification by Ras. Blood 2007; 109:4461–69; PMID:17255356; http://dx.doi.org/10.1182/blood-2006-09-047217
  • Aihara H, Asaoka Y, Yoshida K, Nishizuka Y. Sustained activation of protein kinase C is essential to HL-60 cell differentiation to macrophage. Proc Natl Acad Sci U S A 1991; 88:11062–66; PMID:1763021; http://dx.doi.org/10.1073/pnas.88.24.11062
  • Zabkiewicz J, Pearn L, Hills RK, Morgan RG, Tonks A, Burnett AK, Darley RL. The PDK1 master kinase is over-expressed in acute myeloid leukemia and promotes PKC-mediated survival of leukemic blasts. Haematologica 2014; 99:858–64; PMID:24334295; http://dx.doi.org/10.3324/haematol.2013.096487
  • Bain J, Plater L, Elliott M, Shpiro N, Hastie CJ, McLauchlan H, Klevernic I, Arthur JS, Alessi DR, Cohen P. The selectivity of protein kinase inhibitors: a further update. Biochem J 2007; 408:297–315; PMID:17850214; http://dx.doi.org/10.1042/BJ20070797
  • Clark K, Plater L, Peggie M, Cohen P. Use of the pharmacological inhibitor BX795 to study the regulation and physiological roles of TBK1 and IkappaB kinase epsilon: a distinct upstream kinase mediates Ser-172 phosphorylation and activation. J Biol Chem 2009; 284:14136–46; PMID:19307177; http://dx.doi.org/10.1074/jbc.M109.000414
  • Medina JR, Becker CJ, Blackledge CW, Duquenne C, Feng Y, Grant SW, Heerding D, Li WH, Miller WH, Romeril SP, et al. Structure-based design of potent and selective 3-phosphoinositide-dependent kinase-1 (PDK1) inhibitors. J Med Chem 2011; 54:1871–95; PMID:21341675; http://dx.doi.org/10.1021/jm101527u
  • Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149:274–93; PMID:22500797; http://dx.doi.org/10.1016/j.cell.2012.03.017
  • Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011; 12:21–35; PMID:21157483; http://dx.doi.org/10.1038/nrm3025
  • Hara K, Yonezawa K, Kozlowski MT, Sugimoto T, Andrabi K, Weng QP, Kasuga M, Nishimoto I, Avruch J. Regulation of eIF-4E BP1 phosphorylation by mTOR. J Biol Chem 1997; 272:26457–63; PMID:9334222; http://dx.doi.org/10.1074/jbc.272.42.26457
  • Yee KW, Zeng Z, Konopleva M, Verstovsek S, Ravandi F, Ferrajoli A, Thomas D, Wierda W, Apostolidou E, Albitar M, et al. Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2006; 12:5165–73; PMID:16951235; http://dx.doi.org/10.1158/1078-0432.CCR-06-0764
  • Bohm A, Aichberger KJ, Mayerhofer M, Herrmann H, Florian S, Krauth MT, Derdak S, Samorapoompichit P, Sonneck K, Vales A, et al. Targeting of mTOR is associated with decreased growth and decreased VEGF expression in acute myeloid leukaemia cells. Eur J Clin Invest 2009; 39:395–405; PMID:19320940; http://dx.doi.org/10.1111/j.1365-2362.2009.02101.x
  • Perl AE, Kasner MT, Tsai DE, Vogl DT, Loren AW, Schuster SJ, Porter DL, Stadtmauer EA, Goldstein SC, Frey NV, et al. A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia. Clin Cancer Res 2009; 15:6732–9; PMID:19843663; http://dx.doi.org/10.1158/1078-0432.CCR-09-0842
  • Janus A, Linke A, Cebula B, Robak T, Smolewski P. Rapamycin, the mTOR kinase inhibitor, sensitizes acute myeloid leukemia cells, HL-60 cells, to the cytotoxic effect of arabinozide cytarabine. Anticancer Drugs 2009; 20:693–701; PMID:19584709; http://dx.doi.org/10.1097/CAD.0b013e32832e89b4
  • Callera F, Lopes CO, Rosa ES, Mulin CC. Lack of antileukemic activity of rapamycin in elderly patients with acute myeloid leukemia evolving from a myelodysplastic syndrome. Leuk Res 2008; 32:1633–4; PMID:18405970; http://dx.doi.org/10.1016/j.leukres.2008.02.004
  • Boehm A, Mayerhofer M, Herndlhofer S, Knoebl P, Sillaber C, Sperr WR, Jaeger U, Valent P. Evaluation of in vivo antineoplastic effects of rapamycin in patients with chemotherapy-refractory AML. Eur J Intern Med 2009; 20:775–8; PMID:19892307; http://dx.doi.org/10.1016/j.ejim.2009.09.007
  • Liesveld JL, O'Dwyer K, Walker A, Becker MW, Ifthikharuddin JJ, Mulford D, Chen R, Bechelli J, Rosell K, Minhajuddin M, et al. A phase I study of decitabine and rapamycin in relapsed/refractory AML. Leuk Res 2013; 37:1622–7; PMID:24138944; http://dx.doi.org/10.1016/j.leukres.2013.09.002
  • Rizzieri DA, Feldman E, Dipersio JF, Gabrail N, Stock W, Strair R, Rivera VM, Albitar M, Bedrosian CL, Giles FJ. A phase 2 clinical trial of deforolimus (AP23573, MK-8669), a novel mammalian target of rapamycin inhibitor, in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 2008; 14:2756–62; PMID:18451242; http://dx.doi.org/10.1158/1078-0432.CCR-07-1372
  • Park S, Chapuis N, Saint Marcoux F, Recher C, Prebet T, Chevallier P, Cahn JY, Leguay T, Bories P, Witz F, et al. A phase Ib GOELAMS study of the mTOR inhibitor RAD001 in association with chemotherapy for AML patients in first relapse. Leukemia 2013; 27:1479–86; PMID:23321953; http://dx.doi.org/10.1038/leu.2013.17
  • Amadori S, Stasi R, Martelli AM, Venditti A, Meloni G, Pane F, Martinelli G, Lunghi M, Pagano L, Cilloni D, et al. Temsirolimus, an mTOR inhibitor, in combination with lower-dose clofarabine as salvage therapy for older patients with acute myeloid leukaemia: results of a phase II GIMEMA study (AML-1107). Br J Haematol 2012; 156:205–12; PMID:22082314; http://dx.doi.org/10.1111/j.1365-2141.2011.08940.x
  • Altman JK, Sassano A, Kaur S, Glaser H, Kroczynska B, Redig AJ, Russo S, Barr S, Platanias LC. Dual mTORC2/mTORC1 targeting results in potent suppressive effects on acute myeloid leukemia (AML) progenitors. Clin Cancer Res 2011; 17:4378–88; PMID:21415215; http://dx.doi.org/10.1158/1078-0432.CCR-10-2285
  • Willems L, Chapuis N, Puissant A, Maciel TT, Green AS, Jacque N, Vignon C, Park S, Guichard S, Herault O, et al. The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia. Leukemia 2012; 26:1195–202; PMID:22143671; http://dx.doi.org/10.1038/leu.2011.339
  • Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by up-regulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood 2008; 111:379–82; PMID:17878402; http://dx.doi.org/10.1182/blood-2007-03-080796
  • Zeng Z, Wang R-Y, Shi Y, Qiu Y, Mak DH, Coombes K, Yoo SY, Jessen K, Liu Y, Rommel C, et al. MLN0128, a second-generation mTOR kinase inhibitor, disrupts survival signaling and triggers apoptosis in AML. Blood 2014; 124: abstract 3613; PMID:25261197; http://dx.doi.org/10.1182/blood-2014-01-551457
  • Jain N, Curran E, Iyengar NM, Diaz-Flores E, Kunnavakkam R, Popplewell L, Kirschbaum MH, Karrison T, Erba HP, Green M, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res 2014; 20:490–8; PMID:24178622; http://dx.doi.org/10.1158/1078-0432.CCR-13-1311
  • Meja K, Stengel C, Sellar R, Huszar D, Davies BR, Gale RE, Linch DC, Khwaja A. PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways. Br J Haematol 2014; 167:69–79; PMID:24975213; http://dx.doi.org/10.1111/bjh.13013
  • Teo T, Yu M, Yang Y, Gillam T, Lam F, Sykes MJ, Wang S. Pharmacologic co-inhibition of Mnks and mTORC1 synergistically suppresses proliferation and perturbs cell cycle progression in blast crisis chronic myeloid leukemia cells. Cancer Lett 2014; 357:612–23; PMID:25527453; http://dx.doi.org/10.1016/j.canlet.2014.12.029
  • Joshi S, Platanias LC. Mnk kinase pathway: cellular functions and biological outcomes. World J Biol Chem 2014; 5:321–33; PMID:25225600; http://dx.doi.org/10.4331/wjbc.v5.i3.321
  • Altman JK, Szilard A, Goussetis DJ, Sassano A, Colamonici M, Gounaris E, Frankfurt O, Giles FJ, Eklund EA, Beauchamp EM, et al. Autophagy is a survival mechanism of acute myelogenous leukemia precursors during dual mTORC2/mTORC1 targeting. Clin Cancer Res 2014; 20:2400–9; PMID:24610825; http://dx.doi.org/10.1158/1078-0432.CCR-13-3218
  • Wong PM, Puente C, Ganley IG, Jiang X. The ULK1 complex: sensing nutrient signals for autophagy activation. Autophagy 2013; 9:124–37; PMID:23295650; http://dx.doi.org/10.4161/auto.23323
  • Han W, Sun J, Feng L, Wang K, Li D, Pan Q, Chen Y, Jin W, Wang X, Pan H, et al. Autophagy inhibition enhances daunorubicin-induced apoptosis in K562 cells. PLoS One 2011; 6:e28491; PMID:22164300; http://dx.doi.org/10.1371/journal.pone.0028491
  • Bosnjak M, Ristic B, Arsikin K, Mircic A, Suzin-Zivkovic V, Perovic V, Bogdanovic A, Paunovic V, Markovic I, Bumbasirevic V, et al. Inhibition of mTOR-dependent autophagy sensitizes leukemic cells to cytarabine-induced apoptotic death. PLoS One 2014; 9:e94374; PMID:24714637; http://dx.doi.org/10.1371/journal.pone.0094374
  • Amaravadi RK, Winkler JD. Lys05: a new lysosomal autophagy inhibitor. Autophagy 2012; 8:1383–84; PMID:22878685; http://dx.doi.org/10.4161/auto.20958
  • Kaneko M, Nozawa H, Hiyoshi M, Tada N, Murono K, Nirei T, Emoto S, Kishikawa J, Iida Y, Sunami E, et al. Temsirolimus and chloroquine cooperatively exhibit a potent antitumor effect against colorectal cancer cells. J Cancer Res Clin Oncol 2014; 140:769–81; PMID:24619662; http://dx.doi.org/10.1007/s00432-014-1628-0
  • Mahalingam D, Mita M, Sarantopoulos J, Wood L, Amaravadi RK, Davis LE, Mita AC, Curiel TJ, Espitia CM, Nawrocki ST, et al. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors. Autophagy 2014; 10:1403–14; PMID:24991835; http://dx.doi.org/10.4161/auto.29231
  • Sehgal AR, Konig H, Johnson DE, Tang D, Amaravadi RK, Boyiadzis M, Lotze MT. You eat what you are: autophagy inhibition as a therapeutic strategy in leukemia. Leukemia. 2015 Mar; 29(3):517-525; http://dx.doi.org/10.1038/leu.2014.349
  • Duncan JS, Whittle MC, Nakamura K, Abell AN, Midland AA, Zawistowski JS, Johnson NL, Granger DA, Jordan NV, Darr DB, et al. Dynamic reprogramming of the kinome in response to targeted MEK inhibition in triple-negative breast cancer. Cell 2012; 149:307–21; PMID:22500798; http://dx.doi.org/10.1016/j.cell.2012.02.053
  • Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 1998; 12:502–13; PMID:9472019; http://dx.doi.org/10.1101/gad.12.4.502
  • Diab S, Teo T, Kumarasiri M, Li P, Yu M, Lam F, Basnet SK, Sykes MJ, Albrecht H, Milne R, et al. Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation. ChemMedChem 2014; 9:962–72; PMID:24677692; http://dx.doi.org/10.1002/cmdc.201300552
  • Lim S, Saw TY, Zhang M, Janes MR, Nacro K, Hill J, Lim AQ, Chang CT, Fruman DA, Rizzieri DA, et al. Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. Proc Natl Acad Sci U S A 2013; 110:E2298–307; PMID:23737503; http://dx.doi.org/10.1073/pnas.1301838110
  • Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, Sellers WR, Lengauer C, Stegmeier F. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res 2009; 69:4286–93; PMID:19401449; http://dx.doi.org/10.1158/0008-5472.CAN-08-4765
  • Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 2015; 372:30–9; PMID:25399551; http://dx.doi.org/10.1056/NEJMoa1412690

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.