Outlook on PI3K/AKT/mTOR inhibition in acute leukemia
Abstract
Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.
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Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502(7471):333–9.
PubMedCentralPubMedGoogle Scholar
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81.
PubMedGoogle Scholar
Röllig CM, CRöllig C, Müller-Tidow C, Hüttmann A, Noppeney R, Kunzmann V, et al. Sorafenib versus placebo in addition to standard therapy in younger patients with newly diagnosed acute myeloid leukemia: results from 267 patients treated in the randomized placebo-controlled SAL-soraml trial. In: ASH annual meeting and exposition 2014. San Francisco, CA: ASH; 2014.
Google Scholar
Elert E. Living with leukaemia. Nature. 2013;498(7455):S2–3.
PubMedGoogle Scholar
Wattad M. Impact of the composition of salvage regimens on response and overall survival in primary refractory acute myeloid leukemia. In: EHA 19th, June 12–15, 2014. vol. ABSSUB-5216. Milan, Italy: EHA; 2014.
Google Scholar
Gokbuget N, Hoelzer D. Treatment of adult acute lymphoblastic leukemia. Semin Hematol. 2009;46(1):64–75.
PubMedGoogle Scholar
Gokbuget N, Stanze D, Beck J, Diedrich H, Horst HA, Huttmann A, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120(10):2032–41.
PubMedGoogle Scholar
Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK, et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123–31.
PubMedGoogle Scholar
Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243(5405):290–3.
PubMedGoogle Scholar
Lee HJ, Thompson JE, Wang ES, Wetzler M. Philadelphia chromosome-positive acute lymphoblastic leukemia: current treatment and future perspectives. Cancer. 2011;117(8):1583–94.
PubMedGoogle Scholar
Benjamini O, Dumlao TL, Kantarjian H, O'Brien S, Garcia-Manero G, Faderl S, et al. Phase II trial of hyper CVAD and dasatinib in patients with relapsed Philadelphia chromosome positive acute lymphoblastic leukemia or blast phase chronic myeloid leukemia. Am J Hematol. 2014;89(3):282–7.
PubMedCentralPubMedGoogle Scholar
Chomienne C, Cornic M, Castaigne S, Lefebvre P, de The H, Dejean A, et al. Biological parameters of the efficiency of retinoic acid in acute leukemia. C R Seances Soc Biol Fil. 1991;185(6):456–63.
PubMedGoogle Scholar
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111–21.
PubMedGoogle Scholar
Buitenhuis M, Coffer PJ. The role of the PI3K-PKB signaling module in regulation of hematopoiesis. Cell Cycle. 2009;8(4):560–6.
PubMedGoogle Scholar
Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13(2):140–56.
PubMedCentralPubMedGoogle Scholar
Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A. 1997;94(9):4330–5.
PubMedCentralPubMedGoogle Scholar
Tamburini J, Chapuis N, Bardet V, Park S, Sujobert P, Willems L, 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(1):379–82.
PubMedGoogle Scholar
Vanhaesebroeck B, Stephens L, Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol. 2012;13(3):195–203.
PubMedGoogle Scholar
Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennstrom S, et al. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J. 1998;17(3):743–53.
PubMedCentralPubMedGoogle Scholar
Kubota Y, Ohnishi H, Kitanaka A, Ishida T, Tanaka T. Constitutive activation of PI3K is involved in the spontaneous proliferation of primary acute myeloid leukemia cells: direct evidence of PI3K activation. Leukemia. 2004;18(8):1438–40.
PubMedGoogle Scholar
Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood. 2003;102(3):972–80.
PubMedGoogle Scholar
Gritsman K, Yuzugullu H, Von T, Yan H, Clayton L, Fritsch C, et al. Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. J Clin Invest. 2014;124(4):1794–809.
PubMedCentralPubMedGoogle Scholar
Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, et al. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood. 2005;106(3):1063–6.
PubMedGoogle Scholar
Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B, et al. 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(50):6648–59.
PubMedGoogle Scholar
Tamburini J, Elie C, Bardet V, Chapuis N, Park S, Broet P, et al. Constitutive phosphoinositide 3-kinase/Akt activation represents a favorable prognostic factor in de novo acute myelogenous leukemia patients. Blood. 2007;110(3):1025–8.
PubMedGoogle Scholar
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, et al. Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable. Leukemia. 2003;17(5):995–7.
PubMedGoogle Scholar
Gallay N, Dos Santos C, Cuzin L, Bousquet M, Simmonet Gouy V, Chaussade C, et al. 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(6):1029–38.
PubMedGoogle Scholar
Kornblau SM, Womble M, Qiu YH, Jackson CE, Chen W, Konopleva M, et al. Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia. Blood. 2006;108(7):2358–65.
PubMedCentralPubMedGoogle Scholar
Brandts CH, Sargin B, Rode M, Biermann C, Lindtner B, Schwable J, et al. Constitutive activation of Akt by Flt3 internal tandem duplications is necessary for increased survival, proliferation, and myeloid transformation. Cancer Res. 2005;65(21):9643–50.
PubMedGoogle Scholar
Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, et al. Autocrine IGF-1/IGF-1R signaling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Haematologica. 2010;95(3):415–23.
PubMedCentralPubMedGoogle Scholar
Recher C, Dos Santos C, Demur C, Payrastre B. mTOR, a new therapeutic target in acute myeloid leukemia. Cell Cycle. 2005;4(11):1540–9.
PubMedGoogle Scholar
Chow S, Minden MD, Hedley DW. Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients. Exp Hematol. 2006;34(9):1183–91.
PubMedGoogle Scholar
Park S, Chapuis N, Saint Marcoux F, Recher C, Prebet T, Chevallier P, 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(7):1479–86.
PubMedGoogle Scholar
Ley T. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.
Google Scholar
Liu TC, Lin PM, Chang JG, Lee JP, Chen TP, Lin SF. Mutation analysis of PTEN/MMAC1 in acute myeloid leukemia. Am J Hematol. 2000;63(4):170–5.
PubMedGoogle Scholar
Cheong JW, Eom JI, Maeng HY, Lee ST, Hahn JS, Ko YW, et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol. 2003;122(3):454–6.
PubMedGoogle Scholar
Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994;370(6490):527–32.
PubMedGoogle Scholar
Harrison-Findik D, Susa M, Varticovski L. Association of phosphatidylinositol 3-kinase with SHC in chronic myelogeneous leukemia cells. Oncogene. 1995;10(7):1385–91.
PubMedGoogle Scholar
Kharas MG, Janes MR, Scarfone VM, Lilly MB, Knight ZA, Shokat KM, et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J Clin Invest. 2008;118(9):3038–50.
PubMedCentralPubMedGoogle Scholar
Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22(24):8580–91.
PubMedCentralPubMedGoogle Scholar
Gomes AM, Soares MV, Ribeiro P, Caldas J, Povoa V, Martins LR, et al. Adult B-cell acute lymphoblastic leukemia cells display decreased PTEN activity and constitutive hyperactivation of PI3K/Akt pathway despite high PTEN protein levels. Haematologica. 2014;99(6):1062–8.
PubMedCentralPubMedGoogle Scholar
Morishita N, Tsukahara H, Chayama K, Ishida T, Washio K, Miyamura T, et al. Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012;59(1):83–9.
PubMedGoogle Scholar
Brown VI, Fang J, Alcorn K, Barr R, Kim JM, Wasserman R, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003;100(25):15113–8.
PubMedCentralPubMedGoogle Scholar
Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–66.
PubMedCentralPubMedGoogle Scholar
Tasian SK, Doral MY, Borowitz MJ, Wood BL, Chen IM, Harvey RC, et al. Aberrant STAT5 and PI3K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833–42.
PubMedCentralPubMedGoogle Scholar
Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest. 2008;118(11):3762–74.
PubMedCentralPubMedGoogle Scholar
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13(10):1203–10.
PubMedCentralPubMedGoogle Scholar
COSMIC. Sharing Data from Large-scale Biological Research Projects: A System of Tripartite Responsibility. In: COSMIC repository: 2003; Fort Lauderdale, Florida, USA; 2003.
Google Scholar
Gutierrez A, Sanda T, Grebliunaite R, Carracedo A, Salmena L, Ahn Y, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood. 2009;114(3):647–50.
PubMedCentralPubMedGoogle Scholar
Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol. 2013;31(34):4333–42.
PubMedGoogle Scholar
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, et al. NOTCH1 activation clinically antagonizes the unfavorable effect of PTEN inactivation in BFM-treated children with precursor T-cell acute lymphoblastic leukemia. Haematologica. 2013;98(6):928–36.
PubMedCentralPubMedGoogle Scholar
Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell. 2013;24(6):766–76.
PubMedGoogle Scholar
Wee S, Wiederschain D, Maira SM, Loo A, Miller C, deBeaumont R, et al. PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A. 2008;105(35):13057–62.
PubMedCentralPubMedGoogle Scholar
Stengel C, Jenner E, Meja K, Mayekar S, Khwaja A. Proliferation of PTEN-deficient haematopoietic tumour cells is not affected by isoform-selective inhibition of p110 PI3-kinase and requires blockade of all class 1 PI3K activity. Br J Haematol. 2013;162(2):285–9.
PubMedGoogle Scholar
Subramaniam PS, Whye DW, Efimenko E, Chen J, Tosello V, De Keersmaecker K, et al. Targeting nonclassical oncogenes for therapy in T-ALL. Cancer Cell. 2012;21(4):459–72.
PubMedGoogle Scholar
Dibirdik I, Langlie MC, Ledbetter JA, Tuel-Ahlgren L, Obuz V, Waddick KG, et al. Engagement of interleukin-7 receptor stimulates tyrosine phosphorylation, phosphoinositide turnover, and clonal proliferation of human T-lineage acute lymphoblastic leukemia cells. Blood. 1991;78(3):564–70.
PubMedGoogle Scholar
Medyouf H, Gusscott S, Wang H, Tseng JC, Wai C, Nemirovsky O, et al. High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. J Exp Med. 2011;208(9):1809–22.
PubMedCentralPubMedGoogle Scholar
Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, et al. Genome-wide mapping and characterization of notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158(3):593–606.
PubMedGoogle Scholar
Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.
PubMedGoogle Scholar
Notta F, Mullighan CG, Wang JC, Poeppl A, Doulatov S, Phillips LA, et al. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature. 2011;469(7330):362–7.
PubMedGoogle Scholar
Guo W, Lasky JL, Chang CJ, Mosessian S, Lewis X, Xiao Y, et al. Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature. 2008;453(7194):529–33.
PubMedCentralPubMedGoogle Scholar
Cox CV, Martin HM, Kearns PR, Virgo P, Evely RS, Blair A. Characterization of a progenitor cell population in childhood T-cell acute lymphoblastic leukemia. Blood. 2007;109(2):674–82.
PubMedGoogle Scholar
Patel B, Dey A, Castleton AZ, Schwab C, Samuel E, Sivakumaran J, et al. Mouse xenograft modeling of human adult acute lymphoblastic leukemia provides mechanistic insights into adult LIC biology. Blood. 2014;124(1):96–105.
PubMedGoogle Scholar
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17(9):1086–93.
PubMedGoogle Scholar
Guo W, Schubbert S, Chen JY, Valamehr B, Mosessian S, Shi H, et al. Suppression of leukemia development caused by PTEN loss. Proc Natl Acad Sci U S A. 2011;108(4):1409–14.
PubMedCentralPubMedGoogle Scholar
Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475–82.
PubMedGoogle Scholar
Kalaitzidis D, Sykes SM, Wang Z, Punt N, Tang Y, Ragu C, et al. mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell. 2012;11(3):429–39.
PubMedCentralPubMedGoogle Scholar
Magee JA, Ikenoue T, Nakada D, Lee JY, Guan KL, Morrison SJ. Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell. 2012;11(3):415–28.
PubMedCentralPubMedGoogle Scholar
Hoshii T, Tadokoro Y, Naka K, Ooshio T, Muraguchi T, Sugiyama N, et al. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest. 2012;122(6):2114–29.
PubMedCentralPubMedGoogle Scholar
Blackburn JS, Liu S, Wilder JL, Dobrinski KP, Lobbardi R, Moore FE, et al. Clonal evolution enhances leukemia-propagating cell frequency in T cell acute lymphoblastic leukemia through Akt/mTORC1 pathway activation. Cancer Cell. 2014;25(3):366–78.
PubMedCentralPubMedGoogle Scholar
Guo F, Zhang S, Grogg M, Cancelas JA, Varney ME, Starczynowski DT, et al. Mouse gene targeting reveals an essential role of mTOR in hematopoietic stem cell engraftment and hematopoiesis. Haematologica. 2013;98(9):1353–8.
PubMedCentralPubMedGoogle Scholar
Tamburini J, Green AS, Bardet V, Chapuis N, Park S, Willems L, et al. Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia. Blood. 2009;114(8):1618–27.
PubMedGoogle Scholar
Martel RR, Klicius J, Galet S. Inhibition of the immune response by rapamycin, a new antifungal antibiotic. Can J Physiol Pharmacol. 1977;55(1):48–51.
PubMedGoogle Scholar
Xu Q, Thompson JE, Carroll M. mTOR regulates cell survival after etoposide treatment in primary AML cells. Blood. 2005;106(13):4261–8.
PubMedCentralPubMedGoogle Scholar
Zeng Z, dos Sarbassov D, Samudio IJ, Yee KW, Munsell MF, Ellen Jackson C, et al. Rapamycin derivatives reduce mTORC2 signaling and inhibit AKT activation in AML. Blood. 2007;109(8):3509–12.
PubMedCentralPubMedGoogle Scholar
Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mas VM, et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood. 2005;105(6):2527–34.
PubMedGoogle Scholar
Perl AE, Kasner MT, Tsai DE, Vogl DT, Loren AW, Schuster SJ, 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(21):6732–9.
PubMedGoogle Scholar
Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, et al. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(23):3822–9.
PubMedGoogle Scholar
Amadori S, Stasi R, Martelli AM, Venditti A, Meloni G, Pane F, 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. 2011;156(2):205–12.
PubMedGoogle Scholar
Perl AE, Kasner MT, Shank D, Luger SM, Carroll M. Single-cell pharmacodynamic monitoring of S6 ribosomal protein phosphorylation in AML blasts during a clinical trial combining the mTOR inhibitor sirolimus and intensive chemotherapy. Clin Cancer Res. 2011;18(6):1716–25.
PubMedCentralPubMedGoogle Scholar
Naval Daver M, Kantarjian HM, Thomas DA, Rytting ME, Farhad R, Nitin J, et al. A phase I/II study of hyper-CVAD plus everolimus in patients with relapsed/refractory acute lymphoblastic leukemia. In: ASH annual meeting and exposition. New Orleans: ASH; 2013.
Google Scholar
O'Brien S, Thomas D, Ravandi F, Faderl S, Cortes J, Borthakur G, et al. Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer. 2008;113(11):3186–91.
PubMedCentralPubMedGoogle Scholar
Hoshii T, Kasada A, Hatakeyama T, Ohtani M, Tadokoro Y, Naka K, et al. Loss of mTOR complex 1 induces developmental blockage in early T-lymphopoiesis and eradicates T-cell acute lymphoblastic leukemia cells. Proc Natl Acad Sci U S A. 2014;111(10):3805–10.
PubMedCentralPubMedGoogle Scholar
Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 2009;7(2):e38.
PubMedGoogle Scholar
Janes MR, Vu C, Mallya S, Shieh MP, Limon JJ, Li LS, et al. Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia. 2013;27(3):586–94.
PubMedCentralPubMedGoogle Scholar
Garcia-Martinez JM, Moran J, Clarke RG, Gray A, Cosulich SC, Chresta CM, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J. 2009;421(1):29–42.
PubMedCentralPubMedGoogle Scholar
Ezell SA, Mayo M, Bihani T, Tepsuporn S, Wang S, Passino M, et al. Synergistic induction of apoptosis by combination of BTK and dual mTORC1/2 inhibitors in diffuse large B cell lymphoma. Oncotarget. 2014;5(13):4990–5001.
PubMedCentralPubMedGoogle Scholar
Ashworth RE, Wu J. Mammalian target of rapamycin inhibition in hepatocellular carcinoma. World J Hepatol. 2014;6(11):776–82.
PubMedCentralPubMedGoogle Scholar
Sampath D, Cortes J, Estrov Z, Du M, Shi Z, Andreeff M, et al. Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial. Blood. 2006;107(6):2517–24.
PubMedCentralPubMedGoogle Scholar
Gojo I, Perl A, Luger S, Baer MR, Norsworthy KJ, Bauer KS, et al. 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(5):1217–27.
PubMedCentralPubMedGoogle Scholar
Sampath D, Malik A, Plunkett W, Nowak B, Williams B, Burton M, 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(11):1461–7.
PubMedCentralPubMedGoogle Scholar
Fruman DA, Cantley LC. Idelalisib–a PI3Kdelta inhibitor for B-cell cancers. N Engl J Med. 2014;370(11):1061–2.
PubMedCentralPubMedGoogle Scholar
Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.
PubMedCentralPubMedGoogle Scholar
Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18.
PubMedCentralPubMedGoogle Scholar
Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603–12.
PubMedGoogle Scholar
Lopez JP, Jimeno A. Idelalisib for the treatment of indolent non-Hodgkin's lymphoma. Drugs Today (Barc). 2014;50(2):113–20.
Google Scholar
Nathalie Y, Rosin P, Ekaterina K, Koehrer S, Wang Z, O'Brien S, et al. The PI3K delta inhibitor idelalisib interferes with pre-B cell receptor signaling in acute lymphoblastic leukemia (ALL): a new therapeutic concept. In: ASH annual meeting and exposition. New Orleans: ASH; 2013.
Google Scholar
Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, et al. CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591–4.
PubMedCentralPubMedGoogle Scholar
Xiaoyan Huang M, Proctor J, Yang Y, Gao X, Zhang W, Huang S, et al. The potent PI3K-δ,γ inhibitor, IPI-145, exhibits preclinical activity in murine and human T-cell acute lymphoblastic leukemia. In: ASH annual meeting and exposition. New Orleans, LA: ASH; 2013.
Google Scholar
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia. 2004;18(2):189–218.
PubMedGoogle Scholar
Vachhani P, Bose P, Rahmani M, Grant S. Rational combination of dual PI3K/mTOR blockade and Bcl-2/-xL inhibition in AML. Physiol Genomics. 2014;46(13):448–56.
PubMedGoogle Scholar
Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov. 2014;4(3):334–47.
PubMedCentralPubMedGoogle Scholar
Smith GC, Ong WK, Costa JL, Watson M, Cornish J, Grey A, et al. Extended treatment with selective phosphatidylinositol 3-kinase and mTOR inhibitors has effects on metabolism, growth, behaviour and bone strength. FEBS J. 2013;280(21):5337–49.
PubMedGoogle Scholar
De Buck SS, Jakab A, Boehm M, Bootle D, Juric D, Quadt C, et al. Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies. Br J Clin Pharmacol. 2014;78(3):543–55.
PubMedGoogle Scholar
Brown JR, Byrd JC, Coutre SE, Benson DM, Flinn IW, Wagner-Johnston ND, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110delta, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390–7.
PubMedGoogle Scholar
Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR, et al. A phase 1 study of the PI3Kdelta inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood. 2014;123(22):3398–405.
PubMedGoogle Scholar
Naval Daver HK, DeBose LK, Jabbour E, Borthakur G, Pemmaraju N, Garcia-Manero G, et al. Buparlisib, a PI3K inhibitor, demonstrates acceptable tolerability and preliminary activity in a phase I/II trial of patients with advanced leukemias. In: EHA 19. Milan, Italy: EHA; 2014.
Google Scholar
Lonetti AAC, Spartà AM, Bressanin D, Francesca B, Francesca C, Evangelisti C, et al. Inhibition of class I phosphatidylinositol 3-kinases (pi3ks) isoforms in t-cell acute lymphoblastic leukemia (t-all): which is the best therapeutic strategy? In: 19th annual meeting of EHA. Milan, Italy. 2014.
Google Scholar
Lonetti A, Antunes IL, Chiarini F, Orsini E, Buontempo F, Ricci F, et al. Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia. Leukemia. 2014;28(6):1196–206.
PubMedGoogle Scholar
Dail MP, Wong J, Lawrence J, O'Connor D, Nakitandwe J, Chen S-C, et al. Preclinical testing of a PI3K inhibitor in T lineage leukemia: target validation and Notch1/Myc down-regulation in drug resistant clones. In: ASH annual meeting and exposition. New Orleans, LA: ASH; 2013.
Google Scholar
Wunderle LM, Badura S, Lang F, Wolf A, Schleyer E, Serve H, et al. 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. In: ASH annual meeting and exposition. New Orleans: ASH; 2013.
Google Scholar
Tasian SKM, Li Y, Ryan T, Vincent T, Teachey DT, Loh ML, et al. In vivo efficacy of PI3K pathway signaling inhibition for Philadelphia chromosome-like acute lymphoblastic leukemia. In: ASH annual meeting and exposition. New Orleans, USA: ASH; 2013.
Google Scholar
Badura S, Tesanovic T, Pfeifer H, Wystub S, Nijmeijer BA, Liebermann M, et al. Differential effects of selective inhibitors targeting the PI3K/AKT/mTOR pathway in acute lymphoblastic leukemia. PLoS One. 2013;8(11):e80070.
PubMedCentralPubMedGoogle Scholar
Okabe S, Tauchi T, Tanaka Y, Kitahara T, Kimura S, Maekawa T, et al. Efficacy of the dual PI3K and mTOR inhibitor NVP-BEZ235 in combination with nilotinib against BCR-ABL-positive leukemia cells involves the ABL kinase domain mutation. Cancer Biol Ther. 2014;15(2):207–15.
PubMedCentralPubMedGoogle Scholar
Schult C, Dahlhaus M, Glass A, Fischer K, Lange S, Freund M, et al. The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells. Anticancer Res. 2012;32(2):463–74.
PubMedGoogle Scholar
Chiarini F, Fala F, Tazzari PL, Ricci F, Astolfi A, Pession A, et al. Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. Cancer Res. 2009;69(8):3520–8.
PubMedGoogle Scholar
Shepherd C, Banerjee L, Cheung CW, Mansour MR, Jenkinson S, Gale RE, et al. PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. Leukemia. 2013;27(3):650–60.
PubMedGoogle Scholar
Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, et al. NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008;68(19):8022–30.
PubMedGoogle Scholar
Medvetz D, Priolo C, Henske EP. Therapeutic targeting of cellular metabolism in cells with hyperactive mTORC1: a paradigm shift. Mol Cancer Res. 2015;13(1):3–8.
PubMedGoogle Scholar
Bertacchini J, Guida M, Accordi B, Mediani L, Martelli AM, Barozzi P, 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(11):2197–205.
PubMedGoogle Scholar
Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF. The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol. 1999;19(9):6195–206.
PubMedCentralPubMedGoogle Scholar
Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem. 2000;275(15):10761–6.
PubMedGoogle Scholar
Rahmani M, Aust MM, Attkisson E, Williams Jr DC, Ferreira-Gonzalez A, Grant S. Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism. Cancer Res. 2013;73(4):1340–51.
PubMedCentralPubMedGoogle Scholar
Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci U S A. 2009;106(43):18351–6.
PubMedCentralPubMedGoogle Scholar
Fan AC, O'Rourke JJ, Praharaj DR, Felsher DW. Real-time nanoscale proteomic analysis of the novel multi-kinase pathway inhibitor rigosertib to measure the response to treatment of cancer. Expert Opin Investig Drugs. 2013;22(11):1495–509.
PubMedCentralPubMedGoogle Scholar
Seetharam M, Fan AC, Tran M, Xu L, Renschler JP, Felsher DW, et al. Treatment of higher risk myelodysplastic syndrome patients unresponsive to hypomethylating agents with ON 01910.Na. Leuk Res. 2012;36(1):98–103.
PubMedCentralPubMedGoogle Scholar
Garcia-Manero GM, Fenaux P, Al-Kali A, Baer MR, Sekeres MA, Roboz GJ, et al. Overall survival and subgroup analysis from a randomized phase III study of intravenous rigosertib versus best supportive care (BSC) in patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) after failure of hypomethylating agents (HMAs). In: ASH annual meeting and exposition. San Francisco, CA: ASH; 2014.
Google Scholar
Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature;509(7505):407–11.
Google Scholar
Maecker H. Harnessing the power of the immune system to treat cancer. Berlin: BCRT, Regenerative Immunology and Aging; 2014.
Google Scholar
Dreyling MMF, Bron D, Bouabdallah K, Vitolo U, Linton K, Van den Neste E, et al. Preliminary results of a phase II study of single agent bay 80–6946, a novel PI3K inhibitor, in patients with relapsed/refractory, indolent or aggressive lymphoma. In: ASH annual meeting and exposition. New Orleans, LA: ASH; 2013.
Google Scholar
Roschewski M, Farooqui M, Aue G, Wilhelm F, Wiestner A. Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies. Leukemia. 2013;27(9):1920–3.
PubMedCentralPubMedGoogle Scholar
Komrokji RS, Raza A, Lancet JE, Ren C, Taft D, Maniar M, et al. Phase I clinical trial of oral rigosertib in patients with myelodysplastic syndromes. Br J Haematol. 2013;162(4):517–24.
PubMedGoogle Scholar
Zeng Z, Samudio IJ, Zhang W, Estrov Z, Pelicano H, Harris D, et al. Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. Cancer Res. 2006;66(7):3737–46.
PubMedGoogle Scholar
Friedman DR, Lanasa MC, Davis PH, Allgood SD, Matta KM, Brander DM, et al. Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies. Leuk Lymphoma. 2014;55(5):1067–75.
PubMedGoogle Scholar
Dumble M, Crouthamel MC, Zhang SY, Schaber M, Levy D, Robell K, et al. Discovery of novel AKT inhibitors with enhanced anti-tumor effects in combination with the MEK inhibitor. PLoS One. 2014;9(6):e100880.
PubMedCentralPubMedGoogle Scholar
Levy DS, Kahana JA, Kumar R. AKT inhibitor, GSK690693, induces growth inhibition and apoptosis in acute lymphoblastic leukemia cell lines. Blood. 2009;113(8):1723–9.
PubMedGoogle Scholar

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