Targeting PI3-kinase (PI3K), AKT and mTOR axis in lymphoma

British Journal of Haematology

Volumn 167, Issue 1, 2014, Pages 19-32

  Blachly, James S ^a   Baiocchi, Robert A ^a  

^a THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

Author keywords

AKT; Lymphoma; MTOR; PI3K; Targeted therapy

Indexed keywords

8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; AEZS 136; ALPELISIB; AMG 319; APITOLISIB; BUPARLISIB; BX 912; COPANLISIB; DACTOLISIB; DUVELISIB; EVEROLIMUS; GS 9820; IDELALISIB; IPATASERTIB; MAMMALIAN TARGET OF RAPAMYCIN; MILTEFOSINE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PICTILISIB; PILARALISIB; PLACEBO; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; RITUXIMAB; RP 6530; TEMSIROLIMUS; TGR 1202; UNCLASSIFIED DRUG; UNINDEXED DRUG; ANTINEOPLASTIC AGENT; TARGET OF RAPAMYCIN KINASE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER COMBINATION CHEMOTHERAPY; CARCINOGENESIS; CHRONIC LYMPHATIC LEUKEMIA; DIARRHEA; DOSE RESPONSE; DRUG RESPONSE; DRUG TARGETING; ENZYME INHIBITION; FATIGUE; GENE MUTATION; HEMATOLOGIC MALIGNANCY; HODGKIN DISEASE; HUMAN; HYPERTRANSAMINASEMIA; INFECTION; LARGE CELL LYMPHOMA; LIVER TOXICITY; LYMPHOCYTOMA; LYMPHOMA; MANTLE CELL LYMPHOMA; MOLECULARLY TARGETED THERAPY; NONHODGKIN LYMPHOMA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RASH; RESPIRATORY TRACT INFECTION; SOLID TUMOR; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; LYMPHOMA, NON-HODGKIN; METABOLISM; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

ANIMALS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; HUMANS; LYMPHOMA; LYMPHOMA, NON-HODGKIN; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS C-AKT; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME;

EID: 84909945696     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/bjh.13065     Document Type: Article

References (94)

1. Angulo, I., Vadas, O., Garçon, F., Banham-Hall, E., Plagnol, V., Leahy, T.R., Baxendale, H., Coulter, T., Curtis, J., Wu, C., Blake-Palmer, K., Perisic, O., Smyth, D., Maes, M., Fiddler, C., Juss, J., Cilliers, D., Markelj, G., Chandra, A., Farmer, G., Kielkowska, A., Clark, J., Kracker, S., Debré, M., Picard, C., Pellier, I., Jabado, N., Morris, J.A., Barcenas-Morales, G., Fischer, A., Stephens, L., Hawkins, P., Barrett, J.C., Abinun, M., Clatworthy, M., Durandy, A., Doffinger, R., Chilvers, E.R., Cant, A.J., Kumararatne, D., Okkenhaug, K., Williams, R.L., Condliffe, A. & Nejentsev, S. (2013) Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science (New York, N.Y.), 342, 866-871.
2. Ansell, S.M., Tang, H., Kurtin, P.J., Koenig, P.A., Inwards, D.J., Shah, K., Ziesmer, S.C., Feldman, A.L., Rao, R., Gupta, M., Erlichman, C. & Witzig, T.E. (2011) Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. The Lancet Oncology, 12, 361-368.
3. Bai, H., Wei, J., Deng, C., Yang, X., Wang, C. & Xu, R. (2013) MicroRNA-21 regulates the sensitivity of diffuse large B-cell lymphoma cells to the CHOP chemotherapy regimen. International Journal of Hematology, 97, 223-231.
4. Barrientos, J.C., Wagner-Johnston, N.D., Vos, S.D., Coutre, S.E., Schreeder, M.T., Flinn, I., Sharman, J.P., Rai, K.R., Leonard, J.P., Dansey, R., Kim, Y., Holes, L.M., Adewoye, H. & Furman, R.R. (2013) Chemo-immunotherapy combination of idelalisib with bendamustine/rituximab or chlorambucil/rituximab in patients with relapsed/refractory CLL demonstrates efficacy and tolerability. Blood, 122, 4176.
5. Beer-Hammer, S., Zebedin, E., von Holleben, M., Alferink, J., Reis, B., Dresing, P., Degrandi, D., Scheu, S., Hirsch, E., Sexl, V., Pfeffer, K., Nürnberg, B. & Piekorz, R.P. (2010) The catalytic PI3K isoforms p110γ and p110δ contribute to B cell development and maintenance, transformation, and proliferation. Journal of Leukocyte Biology, 87, 1083-1095.
6. Benson, D., Kahl, B., Furman, R., Brown, J., Wagner-Johnston, N., Coutre, S., Spurgeon, S., Byrd, J., Leonard, J., Peterman, S., Johnson, D., Cho, Y., Dansey, R., Godfrey, W. & Flinn, I. (2013) Final results of a phase I study of idelalisib, a selective inhibitor of PI3K{delta}, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). Journal of Clinical Oncology, 31, 8526.
7. Bodo, J., Zhao, X., Sharma, A., Hill, B.T., Portell, C.A., Lannutti, B.J., Almasan, A. & Hsi, E.D. (2013) The phosphatidylinositol 3-kinases (PI3K) inhibitor GS-1101 synergistically potentiates histone deacetylase inhibitor-induced proliferation inhibition and apoptosis through the inactivation of PI3K and extracellular signal-regulated kinase pathways. British Journal of Haematology, 163, 72-80.
8. Brown, J., Furman, R., Flinn, I., Coutre, S., Wagner-Johnson, N., Kahl, B., Spurgeon, S., Benson, D., Peterman, S., Johnson, D., Li, D., Dansey, R., Jahn, T. & Byrd, J. (2013a) Final results of a phase I study of idelalisib (GSE1101) a selective inhibitor of PI3K{delta}, in patients with relapsed or refractory CLL. Journal of Clinical Oncology, 31, 7003.
9. Brown, J., Davids, M.S., Rodon, J., Abrisqueta, P., Egile, C., Ruiz-Soto, R. & Awan, F. (2013b) Update on the safety and efficacy of the pan class I PI3K inhibitor SAR245408 (XL147) in chronic lymphocytic leukemia and non-Hodgkin's lymphoma patients. Blood, 122, 4170.
10. Brunet, A., Bonni, A., Zigmond, M.J., Lin, M.Z., Juo, P., Hu, L.S., Anderson, M.J., Arden, K.C., Blenis, J. & Greenberg, M.E. (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96, 857-868.
11. Castel, P., Juric, D., Won, H., Ainscough, B., Ellis, H., Ebbesen, S., Griffith, M., Griffith, O., Gopakumar, I., Sgroi, D., Isakoff, S., Mardis, E., Solit, D., Lowe, S., Quadt, C., Peters, M., Berger, M., Scaltriti, M. & Baselga, J. (2014) Loss of PTEN leads to clinical resistance to the PI3Ka inhibitor BYL719 and provides evidence of convergent evolution under selective therapeutic pressure [abstract]. In Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 April 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract LB-327.
12. Chang, B.Y., Furman, R.R., Zapatka, M., Barrientos, J.C., Li, D., Steggerda, S., Eckert, K., Francesco, M., Woyach, J.A., Johnson, A.J., James, D.F., Versele, M., Byrd, J.C., Stilgenbauer, S. & Buggy, J.J. (2013) Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL). Journal of Clinical Oncology, 31(suppl), abstr 7014.
13. Cristofoletti, C., Picchio, M.C., Lazzeri, C., Tocco, V., Pagani, E., Bresin, A., Mancini, B., Passarelli, F., Facchiano, A., Scala, E., Lombardo, G.A., Cantonetti, M., Caprini, E., Russo, G. & Narducci, M.G. (2013) Comprehensive analysis of PTEN status in Sézary syndrome. Blood, 122, 3511-3520.
14. Cross, D.A.E., Alessi, D.R., Cohen, P., Andjelkovich, M. & Hemmings, B.A. (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 378, 785-789.
15. Dal Col, J., Zancai, P., Terrin, L., Guidoboni, M., Ponzoni, M., Pavan, A., Spina, M., Bergamin, S., Rizzo, S., Tirelli, U., De Rossi, A., Doglioni, C. & Dolcetti, R. (2008) Distinct functional significance of Akt and mTOR constitutive activation in mantle cell lymphoma. Blood, 111, 5142-5151.
16. Daley, G.Q., Van Etten, R.A. & Baltimore, D. (1990) Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science (New York, N.Y.), 247, 824-830.
17. Davis, R.E., Ngo, V.N., Lenz, G., Tolar, P., Young, R.M., Romesser, P.B., Kohlhammer, H., Lamy, L., Zhao, H., Yang, Y., Xu, W., Shaffer, A.L., Wright, G., Xiao, W., Powell, J., Jiang, J.-K., Thomas, C.J., Rosenwald, A., Ott, G., Muller-Hermelink, H.K., Gascoyne, R.D., Connors, J.M., Johnson, N.A., Rimsza, L.M., Campo, E., Jaffe, E.S., Wilson, W.H., Delabie, J., Smeland, E.B., Fisher, R.I., Braziel, R.M., Tubbs, R.R., Cook, J.R., Weisenburger, D.D., Chan, W.C., Pierce, S.K. & Staudt, L.M. (2010) Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature, 463, 88-92.
18. Dengler, M.A., Weilbacher, A., Gutekunst, M., Staiger, A.M., Vöhringer, M.C., Horn, H., Ott, G., Aulitzky, W.E. & van der Kuip, H. (2014) Discrepant NOXA (PMAIP1) transcript and NOXA protein levels: a potential Achilles' heel in mantle cell lymphoma. Cell Death & Disease, 5, e1013.
19. Douglas, M., Allison, K., Ted, S., Allen, K., Kahl, B.S., Horwitz, S.M., Flinn, I.W., Kelly, P. & Stern, H.M. (2013) Treatment with the potent PI3K-δ, γ inhibitor IPI-145 is associated with rapid decreases in specific cytokines, chemokines and matrix metalloproteinases in the serum of patients with chronic lymphocytic leukemia and indolent non-Hodgkin lymphoma. Blood, 122, 1633.
20. Dreyling, M., Morschhauser, F., Bron, D., Bouabdallah, K., Vitolo, U., Linton, K., Neste, E.V.D., Mappa, S., Giurescu, M., Childs, B.H. & Zinzani, P.L. (2013) 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. Blood, 122, 87.
21. Furman, R.R., Sharman, J.P., Coutre, S.E., Cheson, B.D., Pagel, J.M., Hillmen, P., Barrientos, J.C., Zelenetz, A.D., Kipps, T.J., Flinn, I., Ghia, P., Eradat, H., Ervin, T., Lamanna, N., Coiffier, B., Pettitt, A.R., Ma, S., Stilgenbauer, S., Cramer, P., Aiello, M., Johnson, D.M., Miller, L.L., Li, D., Jahn, T.M., Dansey, R.D., Hallek, M. & O'Brien, S.M. (2014) Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. The New England Journal of Medicine, 370, 997-1007.
22. Garza, S.J., Lira, P., Huang, S.D., Cheng, H., Dann, S.G., VanArsdale, T.L., Fantin, V., Christensen, J. & Kan, J.L. (2014) Identifying a mechanism of acquired resistance to the combined inhibition of PI3K/mTOR and MEK in colorectal carcinoma [abstract]. In Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract 3713.
23. Go, H., Jan, J.-Y., Nam, S.J., Kim, Y.-G., Paik, J.H., Kim, T.M., Heo, D.S., Kim, C.-W. & Jeon, Y.K. (2014) MiR-21 has strong prognostic implications and functions as an oncogenic miR by modulating PI3K/Akt pathway at multiple levels in diffuse large B cell lymphoma [abstract]. In Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract 1490.
24. Gopal, A.K., Kahl, B.S., de Vos, S., Wagner-Johnston, N.D., Schuster, S.J., Jurczak, W.J., Flinn, I.W., Flowers, C.R., Martin, P., Viardot, A., Blum, K.A., Goy, A.H., Davies, A.J., Zinzani, P.L., Dreyling, M., Johnson, D., Miller, L.L., Holes, L., Li, D., Dansey, R.D., Godfrey, W.R. & Salles, G.A. (2014) PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. The New England Journal of Medicine, 370, 1008-1018.
25. Herman, S.E.M., Gordon, A.L., Wagner, A.J., Heerema, N.A., Zhao, W., Flynn, J.M., Jones, J., Andritsos, L., Puri, K.D., Lannutti, B.J., Giese, N.A., Zhang, X., Wei, L., Byrd, J.C. & Johnson, A.J. (2010) Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 116, 2078-2088.
26. Hers, I., Vincent, E.E. & Tavaré, J.M. (2011) Akt signalling in health and disease. Cellular Signalling, 23, 1515-1527.
27. Hess, G., Herbrecht, R., Romaguera, J., Verhoef, G., Crump, M., Gisselbrecht, C., Laurell, A., Offner, F., Strahs, A., Berkenblit, A., Hanushevsky, O., Clancy, J., Hewes, B., Moore, L. & Coiffier, B. (2009) Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 27, 3822-3829.
28. Hirsch, E., Katanaev, V.L., Garlanda, C., Azzolino, O., Pirola, L., Silengo, L., Sozzani, S., Mantovani, A., Altruda, F. & Wymann, M.P. (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science (New York, N.Y.), 287, 1049-1053.
29. Hirsch, E., Bosco, O., Tropel, P., Laffargue, M., Calvez, R., Altruda, F., Wymann, M. & Montrucchio, G. (2001) Resistance to thromboembolism in PI3Kgamma-deficient mice. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 15, 2019-2021.
30. Hobert, J.A. & Eng, C. (2009) PTEN hamartoma tumor syndrome: an overview. Genetics in Medicine: Official Journal of the American College of Medical Genetics, 11, 687-694.
31. Hutter, G., Zimmermann, Y., Giller, V., Zoellner, A.-K., Weigert, O., Hiddemann, W. & Dreyling, M. (2013) High efficiency of the PDPK1-inhibitor, BX912, in MCL. Blood, 122, 3077.
32. Huw, L.-Y., O'Brien, C., Pandita, A., Mohan, S., Spoerke, J.M., Lu, S., Wang, Y., Hampton, G.M., Wilson, T.R. & Lackner, M.R. (2013) Acquired PIK3CA amplification causes resistance to selective phosphoinositide 3-kinase inhibitors in breast cancer. Oncogenesis, 2, e83.
33. Ilic, N., Utermark, T., Widlund, H.R. & Roberts, T.M. (2011) PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis. Proceedings of the National Academy of Sciences of the USA, 108, E699-E708.
34. Iyengar, S., Clear, A., Bödör, C., Maharaj, L., Lee, A., Calaminici, M., Matthews, J., Iqbal, S., Auer, R., Gribben, J. & Joel, S. (2013) P110α-mediated constitutive PI3K signaling limits the efficacy of p110δ-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood, 121, 2274-2284.
35. Johnson, A.J., Yeh, Y.-Y., Smith, L.L., Wagner, A.J., Hessler, J., Gupta, S., Flynn, J., Jones, J., Zhang, X., Bannerji, R., Grever, M.R. & Byrd, J.C. (2012) The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia, 26, 2554-2557.
36. Kahl, B.S., Spurgeon, S.E., Furman, R.R., Flinn, I.W., Coutre, S.E., Brown, J.R., Benson, D.M., Byrd, J.C., Peterman, S., Cho, Y., Yu, A., Godfrey, W.R. & Wagner-Johnston, N.D. (2014) Results of a phase I study of idelalisib, a PI3Kδ inhibitor, in patients with relapsed or refractory mantle cell lymphoma (MCL). Blood, 123, 3398-3405.
37. Kater, A.P., Tonino, S.H., Kersten, M.J., Hagenbeek, A., Spiering, M., van Oers, M.H., Xin, Y., Ramanathan, S., Aiello, M. & Jun, S. (2013) Interim analysis of dose-escalation stage of a phase 1b study evaluating safety and pharmacology of GS-9820, a second-generation, selective, PI3Kd-inhibitor in recurrent lymphoid malignancies. Blood, 122, 2881.
38. Kim, S.J., Kang, H.J., Kim, J.S., Eom, H.-S., Huh, J., Ko, Y.H., Yim, D.-S., Lee, S.-Y., Suh, C. & Kim, W.S. (2011) Phase I study of mTOR inhibitor everolimus plus CHOP in patients with advanced, aggressive T-cell lymphomas. Blood (ASH Annual Meeting Abstracts), 118, 1642.
39. Kim, A., Park, S., Lee, J.-E., Jang, W.-S., Lee, S.-J., Kang, H.J. & Lee, S.-S. (2012) The dual PI3K and mTOR inhibitor NVP-BEZ235 exhibits anti-proliferative activity and overcomes bortezomib resistance in mantle cell lymphoma cells. Leukemia Research, 36, 912-920.
40. Knight, Z.A., Gonzalez, B., Feldman, M.E., Zunder, E.R., Goldenberg, D.D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W.A., Williams, R.L. & Shokat, K.M. (2006) A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell, 125, 733-747.
41. Kohrt, H.E., Sagiv-Barfi, I., Rafiq, S., Herman, S.E.M., Butchar, J.P., Cheney, C., Zhang, X., Buggy, J.J., Muthusamy, N., Levy, R., Johnson, A.J. & Byrd, J.C. (2013) Ibrutinib (PCI-32765) antagonizes rituximab-dependent NK-cell mediated cytotoxicity. Blood, 122, 373.
42. Kops, G.J., de Ruiter, N.D., De Vries-Smits, A.M., Powell, D.R., Bos, J.L. & Burgering, B.M. (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature, 398, 630-634.
43. Kwei, K.A., Baker, J.B. & Pelham, R.J. (2012) Modulators of sensitivity and resistance to inhibition of PI3K identified in a pharmacogenomic screen of the NCI-60 human tumor cell line collection. PLoS ONE, 7, e46518.
44. Lanasa, M.C., Glenn, M., Mato, A.R., Allgood, S.D., Wong, S., Amore, B., Means, G., Stevens, E., Yan, C., Friberg, G. & Goy, A. (2013) First-in-human study of AMG 319, a highly selective, small molecule inhibitor of PI3Kδ, in adult patients with relapsed or refractory lymphoid malignancies. Blood, 122, 678.
45. Lannutti, B.J., Meadows, S.A., Herman, S.E.M., Kashishian, A., Steiner, B., Johnson, A.J., Byrd, J.C., Tyner, J.W., Loriaux, M.M., Deininger, M., Druker, B.J., Puri, K.D., Ulrich, R.G. & Giese, N.A. (2011) CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood, 117, 591-594.
46. Lapalombella, R., Yeh, Y.-Y., Wang, L., Ramanunni, A., Rafiq, S., Jha, S., Staubli, J., Lucas, D.M., Mani, R., Herman, S.E.M., Johnson, A.J., Lozanski, A., Andritsos, L., Jones, J., Flynn, J.M., Lannutti, B., Thompson, P., Algate, P., Stromatt, S., Jarjoura, D., Mo, X., Wang, D., Chen, C.-S., Lozanski, G., Heerema, N.A., Tridandapani, S., Freitas, M.A., Muthusamy, N. & Byrd, J.C. (2012) Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals. Cancer Cell, 21, 694-708.
47. Leupin, N., Cenni, B., Novak, U., Hügli, B., Graber, H.U., Tobler, A. & Fey, M.F. (2003) Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). British Journal of Haematology, 121, 97-100.
48. Lewis, J., Girardi, M., Vakkalanka, S., Viswanadha, S. & Bertoni, F. (2013) RP6530, a dual PI3Kδ/γ inhibitor, attenutates AKT phosphorylation and induces apoptosis in primary cutaneous T cell lymphoma (CTCL) cells. Blood, 122, 4418.
49. Lin, L., Hron, J.D. & Peng, S.L. (2004) Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity, 21, 203-213.
50. Lindhurst, M.J., Sapp, J.C., Teer, J.K., Johnston, J.J., Finn, E.M., Peters, K., Turner, J., Cannons, J.L., Bick, D., Blakemore, L., Blumhorst, C., Brockmann, K., Calder, P., Cherman, N., Deardorff, M.A., Everman, D.B., Golas, G., Greenstein, R.M., Kato, B.M., Keppler-Noreuil, K.M., Kuznetsov, S.A., Miyamoto, R.T., Newman, K., Ng, D., O'Brien, K., Rothenberg, S., Schwartzentruber, D.J., Singhal, V., Tirabosco, R., Upton, J., Wientroub, S., Zackai, E.H., Hoag, K., Whitewood-Neal, T., Robey, P.G., Schwartzberg, P.L., Darling, T.N., Tosi, L.L., Mullikin, J.C. & Biesecker, L.G. (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. The New England Journal of Medicine, 365, 611-619.
51. Locatelli, S.L., Stirparo, G.G., Tartari, S., Saba, E., Rubino, L., Brusamolino, E., Castagna, L., Santoro, A. & Carlo-Stella, C. (2013) The PI3K/ERK dual inhibitor AEZS-136 induces ROS-dependent necroptotic cell death and exerts potent antitumor effects in NOD/SCID mice with Hodgkin lymphoma cell line xenografts. Blood, 122, 3067.
52. Lucas, C.L., Kuehn, H.S., Zhao, F., Niemela, J.E., Deenick, E.K., Palendira, U., Avery, D.T., Moens, L., Cannons, J.L., Biancalana, M., Stoddard, J., Ouyang, W., Frucht, D.M., Rao, V.K., Atkinson, T.P., Agharahimi, A., Hussey, A.A., Folio, L.R., Olivier, K.N., Fleisher, T.A., Pittaluga, S., Holland, S.M., Cohen, J.I., Oliveira, J.B., Tangye, S.G., Schwartzberg, P.L., Lenardo, M.J. & Uzel, G. (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nature Immunology, 15, 88-97.
53. Maira, S.-M., Stauffer, F., Brueggen, J., Furet, P., Schnell, C., Fritsch, C., Brachmann, S., Chène, P., Pover, A.D., Schoemaker, K., Fabbro, D., Gabriel, D., Simonen, M., Murphy, L., Finan, P., Sellers, W. & García-Echeverría, C. (2008) Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Molecular Cancer Therapeutics, 7, 1851-1863.
54. McIntosh, C., Rodriguez, R., Sportelli, P., Miskin, H.P., Vakkalanka, S., Viswanadha, S., Lipstein, M. & O'Connor, O.A. (2013) The PI3K delta inhibitor TGR-1202 and proteasome inhibitor carfilzomib are highly synergistic in killing human B- and T-cell lymphoma cells. Blood, 122, 4421.
55. Muranen, T., Selfors, L.M., Worster, D.T., Iwanicki, M.P., Song, L., Morales, F.C., Gao, S., Mills, G.B. & Brugge, J.S. (2012) Inhibition of PI3K/mTOR leads to adaptive resistance in matrix-attached cancer cells. Cancer Cell, 21, 227-239.
56. Obrador-Hevia, A., Serra-Sitjar, M., Rodríguez, J., Villalonga, P. & Fernández de Mattos, S. (2012) The tumour suppressor FOXO3 is a key regulator of mantle cell lymphoma proliferation and survival. British Journal of Haematology, 156, 334-345.
57. Ocana, A., Vera-Badillo, F., Al-Mubarak, M., Templeton, A.J., Corrales-Sanchez, V., Diez-Gonzalez, L., Cuenca-Lopez, M.D., Seruga, B., Pandiella, A. & Amir, E. (2014) Activation of the PI3K/mTOR/AKT pathway and survival in solid tumors: systematic review and meta-analysis. PLoS ONE, 9, e95219.
58. Okkenhaug, K. & Vanhaesebroeck, B. (2003) PI3K in lymphocyte development, differentiation and activation. Nature Reviews. Immunology, 3, 317-330.
59. Patel, M.R., Kahl, B.S., Horwitz, S.M., Younes, A., Foss, F.M., Oki, Y., Sweeney, J., Allen, K., Faia, K., Kelley, P.F. & Flinn, I. (2013) Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-δ, γ, in patients with relapsed/refractory CLL. Proceedings of American Society of Clinical Oncology, 31(Suppl), abstract 7070.
60. Pfeifer, M., Grau, M., Lenze, D., Wenzel, S.-S., Wolf, A., Wollert-Wulf, B., Dietze, K., Nogai, H., Storek, B., Madle, H., Dörken, B., Janz, M., Dirnhofer, S., Lenz, P., Hummel, M., Tzankov, A. & Lenz, G. (2013) PTEN loss defines a PI3K/AKT pathway-dependent germinal center subtype of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences of the USA, 110, 12420-12425.
61. Psyrri, A., Papageorgiou, S., Liakata, E., Scorilas, A., Rontogianni, D., Kontos, C.K., Argyriou, P., Pectasides, D., Harhalakis, N., Pappa, V., Kolialexi, A., Economopoulou, C., Kontsioti, F., Maratou, E., Dimitriadis, G., Economopoulou, P. & Economopoulos, T. (2009) Phosphatidylinositol 3′-kinase catalytic subunit α gene amplification contributes to the pathogenesis of mantle cell lymphoma. Clinical Cancer Research, 15, 5724-5732.
62. Pyrzynska, B., Bojarczuk, K., Winiarska, M., Bil, J., Miazek, N., Zapala, P., Bobrowicz, M., Dwojak, M., Siernicka, M. & Golab, J. (2013) Inhibitors of Src family and AKT regulate the activity of CD20 promoter. Blood, 122, 1838.
63. Rahmani, M., Aust, M., Wallace, L. & Grant, S. (2013) Inhibition of PI3K/mTOR by BEZ235 dramatically potentiates panobinostat-induced lethality in diffuse large B-cell lymphoma through multiple mechanisms. Blood, 122, 817.
64. Reddy, E.P., Divakar, S.A., Reddy, M.V.R., Cosenza, S.C., Baker, S.J., Akula, B. & Parekh, S. (2014) Targeting of cyclin D/Rb/E2F and PI3K/AKT/MTOR pathways with ON 123300 as a therapeutic strategy for mantle cell lymphoma [abstract]. In Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; 2014. Abstract 4519.
65. Rizzatti, E.G., Falcao, R.P., Panepucci, R.A., Proto-Siqueira, R., Anselmo-Lima, W.T., Okamoto, O.K. & Zago, M.A. (2005) Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K-AKT, WNT and TGFbeta signalling pathways. British Journal of Haematology, 130, 516-526.
66. Rodriguez, V., Kalko, S., Gine, E., Campo, E., Roue, G., Lopez-Guillermo, A., Colomer, D. & Patricia, P.-G. (2013) Follicular dendrytic cells deliver angiogenesis signaling to follicular lymphoma cells that is hampered by the Pan-PI3K inhibitor NVP-BKM120. Blood, 122, 3072.
67. Rommel, C., Camps, M. & Ji, H. (2007) PI3K[delta] and PI3K[gamma]: partners in crime in inflammation in rheumatoid arthritis and beyond? Nature Reviews Immunology, 7, 191-201.
68. Rowley, J.D. (1973) A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and giemsa staining. Nature, 243, 290-293.
69. Sasaki, T., Irie-Sasaki, J., Jones, R.G., Oliveira-dos-Santos, A.J., Stanford, W.L., Bolon, B., Wakeham, A., Itie, A., Bouchard, D., Kozieradzki, I., Joza, N., Mak, T.W., Ohashi, P.S., Suzuki, A. & Penninger, J.M. (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science (New York, N.Y.), 287, 1040-1046.
70. Savona, M., Gutierrez, M., Lanasa, M., Deng, C., Kuhn, J., Sade, L., Miskin, H., Sportelli, P., Vakkalanka, S. & Patel, M. (2013) A phase i dose escalation study of TGR-1202, a novel PI3K-δ inhibitor, for patients with relapsed or refractory hematologic malignancies. Blood, 122, 4373.
71. Shimobayashi, M. & Hall, M.N. (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nature Reviews Molecular Cell Biology, 15, 155-162.
72. Slouzkey, I., Rosenblum, K. & Maroun, M. (2013) Memory of conditioned taste aversion is erased by inhibition of PI3K in the insular cortex. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology, 38, 1143-1153.
73. Smith, S.M., van Besien, K., Karrison, T., Dancey, J., McLaughlin, P., Younes, A., Smith, S., Stiff, P., Lester, E., Modi, S., Doyle, L.A., Vokes, E.E. & Pro, B. (2010) Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: the University of Chicago Phase II consortium. Journal of Clinical Oncology, 28, 4740-4746.
74. Song, M.S., Salmena, L. & Pandolfi, P.P. (2012) The functions and regulation of the PTEN tumour suppressor. Nature Reviews Molecular Cell Biology, 13, 283-296.
75. Spurgeon, S., Wagner-Johnston, N., Furman, R., Flinn, I., Coutre, S., Brown, J., Benson, D., Byrd, J., Leonard, J., Peterman, S., Johnson, D., Gu, J., Dansey, R., Godfrey, W. & Kahl, B. (2013) Final results of a phase I study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110{delta} (PI3K{delta}), in patients with relapsed or refractory mantle cell lymphoma (MCL). Journal of Clinical Oncology, 31, 8519.
76. Staal, S.P. (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proceedings of the National Academy of Sciences of the USA, 84, 5034-5037.
77. Staal, S.P., Hartley, J.W. & Rowe, W.P. (1977) Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proceedings of the National Academy of Sciences of the USA, 74, 3065-3067.
78. Thomson, A.W., Turnquist, H.R. & Raimondi, G. (2009) Immunoregulatory functions of mTOR inhibition. Nature Reviews Immunology, 9, 324-337.
79. Tiacci, E., Trifonov, V., Schiavoni, G., Holmes, A., Kern, W., Martelli, M.P., Pucciarini, A., Bigerna, B., Pacini, R., Wells, V.A., Sportoletti, P., Pettirossi, V., Mannucci, R., Elliott, O., Liso, A., Ambrosetti, A., Pulsoni, A., Forconi, F., Trentin, L., Semenzato, G., Inghirami, G., Capponi, M., Di Raimondo, F., Patti, C., Arcaini, L., Musto, P., Pileri, S., Haferlach, C., Schnittger, S., Pizzolo, G., Foà, R., Farinelli, L., Haferlach, T., Pasqualucci, L., Rabadan, R. & Falini, B. (2011) BRAF mutations in hairy-cell leukemia. The New England Journal of Medicine, 364, 2305-2315.
80. Tohda, C., Nakanishi, R. & Kadowaki, M. (2009) Hyperactivity, memory deficit and anxiety-related behaviors in mice lacking the p85alpha subunit of phosphoinositide-3 kinase. Brain & Development, 31, 69-74.
81. Vakkalanka, S., Viswanadha, S., Gaudio, E., Zucca, E., Bertoni, F., Bernasconi, E., Rossi, D. & Stathis, A. (2013) Dual PI3Kδ/γ inhibition By RP6530 induces apoptosis and cytotoxicity in B-lymphoma cells. Blood, 122, 4411.
82. Vanhaesebroeck, B., Stephens, L. & Hawkins, P. (2012) PI3K signalling: the path to discovery and understanding. Nature Reviews Molecular Cell Biology, 13, 195-203.
83. Vos, S.D., Furman, R.R., Barrientos, J.C., Wagner-Johnston, N.D., Flinn, I., Sharman, J.P., Boyd, T., Leonard, J.P., Dansey, R., Kim, Y., Holes, L.M., Dubowy, R.L. & Coutre, S.E. (2013) Idelalisib, a selective inhibitor of PI3Kδ, in combination with bendamustine, fludarabine or chlorambucil in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Blood, 122, 2878.
84. Walsh, K., McKinney, M.S., Love, C., Liu, Q., Fan, A., Patel, A., Smith, J., Beaven, A., Jima, D.D. & Dave, S.S. (2013) PAK1 mediates resistance to PI3K inhibition in lymphomas. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 19, 1106-1115.
85. Wanner, K., Hipp, S., Oelsner, M., Ringshausen, I., Bogner, C., Peschel, C. & Decker, T. (2006) Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to rituximab. British Journal of Haematology, 134, 475-484.
86. Witzig, T.E., Geyer, S.M., Ghobrial, I., Inwards, D.J., Fonseca, R., Kurtin, P., Ansell, S.M., Luyun, R., Flynn, P.J., Morton, R.F., Dakhil, S.R., Gross, H. & Kaufmann, S.H. (2005) Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. Journal of Clinical Oncology, 23, 5347-5356.
87. Witzig, T.E., Reeder, C.B., LaPlant, B.R., Gupta, M., Johnston, P.B., Micallef, I.N., Porrata, L.F., Ansell, S.M., Colgan, J.P., Jacobsen, E.D., Ghobrial, I.M. & Habermann, T.M. (2011) A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia, 25, 341-347.
88. Wlodarski, P., Kasprzycka, M., Liu, X., Marzec, M., Robertson, E.S., Slupianek, A. & Wasik, M.A. (2005) Activation of mammalian target of rapamycin in transformed B lymphocytes is nutrient dependent but independent of Akt, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, insulin growth factor-1, and serum. Cancer Research, 65, 7800-7808.
89. Woyach, J.A., Johnson, A.J. & Byrd, J.C. (2012) The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood, 120, 1175-1184.
90. Wu, C., Orozco, C., Boyer, J., Leglise, M., Goodale, J., Batalov, S., Hodge, C.L., Haase, J., Janes, J., Huss, J.W. & Su, A.I. (2009) BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biology, 10, R130.
91. Younes, A., Flinn, I.W., Oki, Y., Copland, A., Fattaey, A., Lai, C.-J., Laliberte, R., Voi, M. & Berdeja, J.G. (2013) A first-in-man phase 1 study of CUDC-907, a first-in-class chemically-designed dual inhibitor of PI3K and HDAC in patients with refractory or relapsed lymphoma and multiple myeloma. Blood, 122, 4363.
92. Zent, C.S., LaPlant, B.R., Johnston, P.B., Call, T.G., Habermann, T.M., Micallef, I.N. & Witzig, T.E. (2010) The treatment of recurrent/refract ory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL Cells into the circulation. Cancer, 116, 2201-2207.
93. Zhang, J., Grubor, V., Love, C.L., Banerjee, A., Richards, K.L., Mieczkowski, P.A., Dunphy, C., Choi, W., Au, W.Y., Srivastava, G., Lugar, P.L., Rizzieri, D.A., Lagoo, A.S., Bernal-Mizrachi, L., Mann, K.P., Flowers, C., Naresh, K., Evens, A., Gordon, L.I., Czader, M., Gill, J.I., Hsi, E.D., Liu, Q., Fan, A., Walsh, K., Jima, D., Smith, L.L., Johnson, A.J., Byrd, J.C., Luftig, M.A., Ni, T., Zhu, J., Chadburn, A., Levy, S., Dunson, D. & Dave, S.S. (2013) Genetic heterogeneity of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences of the USA, 110, 1398-1403.
94. Zou, Z.-J., Zhang, R., Fan, L., Wang, L., Fang, C., Zhang, L.-N., Yang, S., Li, Y.-Y., Li, J.-Y. & Xu, W. (2013) Low expression level of phosphatase and tensin homolog deleted on chromosome ten predicts poor prognosis in chronic lymphocytic leukemia. Leukemia & Lymphoma, 54, 1159-1164.