PI3Kδ inhibitors in cancer: Rationale and serendipity merge in the clinic

Cancer Discovery

Volumn 1, Issue 7, 2011, Pages 562-572

  Fruman, David A ^a   Rommel, Christian ^b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b Intellikine   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 (6 AMINO 9 PURINYLMETHYL) 5 METHYL 3 (2 METHYLPHENYL) 3H QUINAZOLIN 4 ONE; 2 MORPHOLINO 8 PHENYLCHROMONE; AMG 319; B CELL ACTIVATING FACTOR; B LYMPHOCYTE RECEPTOR; BENDAMUSTINE; CAL 263; CD19 ANTIGEN; CHEMOKINE; CHEMOKINE RECEPTOR CCR7; CHEMOTAXIS INHIBITOR; CXCL13 CHEMOKINE; DEXAMETHASONE; FIBRONECTIN; FLUDARABINE; G PROTEIN COUPLED RECEPTOR; GROWTH FACTOR RECEPTOR; IDELALISIB; INTERLEUKIN 4; IPI 145; KAR 4141; LENALIDOMIDE; MACROPHAGE INFLAMMATORY PROTEIN 3BETA; ONCOPROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3, 4, 5 TRISPHOSPHATE; PROTEIN TYROSINE KINASE; RITUXIMAB; SECONDARY LYMPHOID TISSUE CHEMOKINE; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; WORTMANNIN; XL 499;

ACUTE GRANULOCYTIC LEUKEMIA; ALLERGIC RHINITIS; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ARTICLE; CARCINOGENESIS; CELL CYCLE ARREST; CELL DEATH; CHRONIC LYMPHATIC LEUKEMIA; DRUG EFFICACY; DRUG SAFETY; GENE OVEREXPRESSION; GLIOBLASTOMA; HEMATOLOGIC MALIGNANCY; HUMAN; IC 50; IMMUNOSURVEILLANCE; KIDNEY CARCINOMA; LEUKEMIA; LYMPHOCYTE; LYMPHOMA CELL; MANTLE CELL LYMPHOMA; MOLECULARLY TARGETED THERAPY; MULTIPLE MYELOMA; NEOPLASM; NEUROENDOCRINE TUMOR; NONHODGKIN LYMPHOMA; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; TUMOR CELL LINE; TUMOR MICROENVIRONMENT;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS, PHASE I AS TOPIC; DRUG EVALUATION, PRECLINICAL; HUMANS; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PURINES; QUINAZOLINONES;

EID: 84857844598     PISSN: 21598274     EISSN: 21598290     Source Type: Journal    
DOI: 10.1158/2159-8290.CD-11-0249     Document Type: Article

References (108)

1. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, et al. Oncogenes and signal transduction. Cell 1991;64:281-302.
2. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 1985;315:239-42.
3. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998;67:481-507.
4. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-75.
5. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol 2010;11:329-41.
6. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-19.
7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-74.
8. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501.
9. Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC Jr, Abraham RT. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. Embo J 1996;15:5256-67.
10. Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, et al. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007;404:15-21.
11. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-47.
12. Agarwal R, Carey M, Hennessy B, Mills GB. PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Invest Drugs 2010;11:615-28.
13. Garcia-Echeverria C, Sellers WR. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008;27:5511-26.
14. Khwaja A. PI3K as a target for therapy in haematological malignancies. Curr Top Microbiol Immunol 2010;347:169-88.
15. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627-44.
16. Marone R, Cmiljanovic V, Giese B, Wymann MP. Targeting phosphoinositide 3-kinase: moving towards therapy. Biochim Biophys Acta 2008;1784:159-85.
17. Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 2010;20:87-90.
18. Workman P, Clarke PA, Raynaud FI, van Montfort RL. Drugging the PI3 Kinome: From Chemical Tools to Drugs in the Clinic. Cancer Res 2010;70:2146-57.
19. Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr Opin Pharmacol 2008;8:393-412.
20. Ruckle T, Schwarz MK, Rommel C. PI3Kgamma inhibition: towards an 'aspirin of the 21st century'? Nat Rev Drug Discov 2006;5:903-18.
21. Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B. Activity of any class IA PI3K isoform can sustain cell proliferation and survival. Proc Natl Acad Sci U S A 2010;107:11381-6.
22. Berndt A, Miller S, Williams O, Le DD, Houseman BT, Pacold JI, et al. The p110delta structure: mechanisms for selectivity and potency of new PI(3)K inhibitors. Nat Chem Biol 2010;6:244.
23. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, et al. The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 2007;318:1744-8.
24. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, et al. Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 2007;317:239-42.
25. Walker EH, Perisic O, Ried C, Stephens L, Williams RL. Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 1999;402:313-20.
26. Zhang X, Vadas O, Perisic O, Anderson KE, Clark J, Hawkins PT, et al. Structure of lipid kinase p110beta/p85beta elucidates an unusual SH2-domain-mediated inhibitory mechanism. Mol Cell 2011;41:567-78.
27. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 2004;64:7678-81.
28. Ligresti G, Militello L, Steelman LS, Cavallaro A, Basile F, Nicoletti F, et al. PIK3CA mutations in human solid tumors: role in sensitivity to various therapeutic approaches. Cell Cycle 2009;8:1352-8.
29. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
30. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6.
31. Liu P, Cheng H, Santiago S, Raeder M, Zhang F, Isabella A, et al. Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat Med 2011;17:1116-20.
32. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005;7:561-73.
33. O'Brien C, Wallin JJ, Sampath D, GuhaThakurta D, Savage H, Punnoose EA, et al. Predictive biomarkers of sensitivity to the phosphatidylinositol 3' kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res 2010;16:3670-83.
34. Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 2011;30:3222-33.
35. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, et al. Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci U S A 2009;106:22299-304.
36. Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, et al. PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther 2011;10:558-65.
37. Niedermeier M, Hennessy BT, Knight ZA, Henneberg M, Hu J, Kurtova AV, et al. Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cellmediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood 2009;113:5549-57.
38. Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, et al. A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J 2011;438:53-62.
39. Kang S, Denley A, Vanhaesebroeck B, Vogt PK. Oncogenic transformation induced by the p110beta,-gamma, and-delta isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci U S A 2006;103:1289-94.
40. Lee SH, Poulogiannis G, Pyne S, Jia S, Zou L, Signoretti S, et al. A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc Natl Acad Sci U S A 2010;107:11002-7.
41. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 2008;454:776-9.
42. Guillermet-Guibert J, Bjorklof K, Salpekar A, Gonella C, Ramadani F, Bilancio A, et al. The p110beta isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110gamma. Proc Natl Acad Sci U S A 2008;105:8292-7.
43. Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, et al. Phosphoinositide 3-kinase p110{beta} activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 2008;1:ra3.
44. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 2009;69:3955-62.
45. Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell 2011;19:715-27.
46. Okkenhaug K, Ali K, Vanhaesebroeck B. Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K. Trends Immunol 2007;28:80-7.
47. Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, et al. Key role of the p110delta isoform of PI3K in antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 2006;107:642-50.
48. Durand CA, Hartvigsen K, Fogelstrand L, Kim S, Iritani S, Vanhaesebroeck B, et al. Phosphoinositide 3-kinase p110delta regulates natural antibody production, marginal zone and B-1 function, and autoantibody responses. J Immunol 2009;183:5673-84.
49. Williams O, Houseman BT, Kunkel EJ, Aizenstein B, Hoffman R, Knight ZA, et al. Discovery of dual inhibitors of the immune cell PI3Ks p110delta and p110gamma: a prototype for new antiinflammatory drugs. Chem Biol 2010;17:123-34.
50. Gold MR, Aebersold R. Both phosphatidylinositol 3-kinase and phosphatidylinositol 4-kinase products are increased by antigen receptor signaling in B cells. J Immunol 1994;152:42-50.
51. Gold MR, Duronio V, Saxena SP, Schrader JW, Aebersold R. Multiple cytokines activate phosphatidylinositol 3-kinase in hemopoietic cells. Association of the enzyme with various tyrosinephosphorylated proteins. J Biol Chem 1994;269:5403-12.
52. Tuveson DA, Carter RH, Soltoff SP, Fearon DT. CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 1993;260:986-9.
53. Ono M, Bolland S, Tempst P, Ravetch JV. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor Fc(gamma)RIIB. Nature 1996;383:263-6.
54. Scharenberg AM, El-Hillal O, Fruman DA, Beitz LO, Li Z, Lin S, et al. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns-3,4,5-P3)/Tec kinase-dependent calcium signaling pathway: a target for SHIPmediated inhibitory signals. EMBO J 1998;17:1961-72.
55. Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, et al. Impaired development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 1999;283:393-7.
56. Suzuki H, Terauchi Y, Fujiwara M, Aizawa S, Yazaki Y, Kadowaki T, et al. Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science 1999;283:390-2.
57. Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in development and activation. J Exp Med 2002;196:753-63.
58. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Wang D, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the receptor complex. Mol Cell Biol 2002;22:8580-91.
59. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T-cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 2002;297:1031-4.
60. Vanhaesebroeck B, Ali K, Bilancio A, Geering B, Foukas LC. Signalling by PI3K isoforms: insights from gene-targeted mice. Trends Biochem Sci 2005;30:194-204.
61. Al-Alwan MM, Okkenhaug K, Vanhaesebroeck B, Hayflick JS, Marshall AJ. Requirement for phosphoinositide 3-kinase p110delta signaling in antigen receptor-mediated antigen presentation. J Immunol 2007;178:2328-35.
62. Rolf J, Bell SE, Kovesdi D, Janas ML, Soond DR, Webb LM, et al. Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J Immunol 2010;185:4042-52.
63. Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, et al. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 2006;25:545-57.
64. Doi T, Obayashi K, Kadowaki T, Fujii H, Koyasu S. PI3K is a negative regulator of IgE production. Int Immunol 2008;20:499-508.
65. Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, et al. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol 2008;122:811-9. e2.
66. Fruman DA, Bismuth G. Fine tuning the immune response with PI3K. Immunol Rev 2009;228:253-72.
67. Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer. Cell 2004;117:787-800.
68. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001;293:2111-4.
69. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large lymphoma. Nature 2010;463:88-92.
70. Efremov DG, Gobessi S, Longo PG. Signaling pathways activated by antigen-receptor engagement in chronic lymphocytic leukemia B-cells. Autoimmun Rev 2007;7:102-8.
71. Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, et al. PI3 kinase signals BCR-dependent mature survival. Cell 2009;139:573-86.
72. Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE, et al. The PI3K isoforms p110alpha and p110delta are essential for pre-receptor signaling and development. Sci Signal 2010;3:ra60.
73. Cyster JG. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu Rev Immunol 2005; 23:127-59.
74. Okada T, Cyster JG. migration and interactions in the early phase of antibody responses. Curr Opin Immunol 2006;18:278-85.
75. Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG. Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 2004;173:2236-40.
76. Okkenhaug K, Fruman DA. PI3Ks in lymphocyte signaling and development. Curr Top Microbiol Immunol 2010;346:57-85.
77. Janas ML, Varano G, Gudmundsson K, Noda M, Nagasawa T, Turner M. Thymic development beyond beta-selection requires phosphatidylinositol 3-kinase activation by CXCR4. J Exp Med 2010;207:247-61, S1--2.
78. Swat W, Montgrain V, Doggett TA, Douangpanya J, Puri K, Vermi W, et al. Essential role of PI3Kdelta and PI3Kgamma in thymocyte survival. Blood 2006;107:2415-22.
79. Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting edge: T-cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol 2005;175:2783-7.
80. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 2006;177:5122-8.
81. Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol 2006;177:6598-602.
82. Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, et al. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood 2010;115:2203-13.
83. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, Marques M, et al. Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 2004;21:429-41.
84. Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, et al. PI3K/p110{delta} is a novel therapeutic target in multiple myeloma. Blood 2010;116:1460-8.
85. 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 malignancies, inhibits PI3K signaling and cellular viability. Blood 2011;117:591-4.
86. Rommel C, Camps M, Ji H. PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Drug Disc 2007;7:191-201.
87. Furman RR, Byrd JC, Brown JR, Coutre SE, Benson DM, Wagner-Johnston ND, et al. CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. ASH Annual Meeting Abstracts 2010;116:55.
88. Furman RR, Byrd JC, Flinn IW, Coutre SE, M. BD, Brown JR, et al. Interim results from a phase I study of CAL-101, a selective oral inhibitor of phosphatidylinositol 3-kinase p110d isoform, in patients with relapsed or refractory hematologic malignancies. J Clin Oncol 2010;28:15s (abstr 3032).
89. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol 2010;28:1075-83.
90. Herman SE, Lapalombella R, Gordon AL, Ramanunni A, Blum KA, Jones J, et al. The role of phosphatidylinositol 3-kinase-delta in the immunomodulatory effects of lenalidomide in chronic lymphocytic leukemia. Blood 2011;117:4323-7.
91. Bousquet M, Recher C, Queleen C, Demur C, Payrastre B, Brousset P. Assessment of somatic mutations in phosphatidylinositol 3-kinase gene in human lymphoma and acute leukaemia. Br J Haematol 2005;131:411-3.
92. Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN gene alterations in lymphoid neoplasms. Blood 1998;92:3410-5.
93. 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;13:1203-10.
94. 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;25:6648-59.
95. 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;106:1063-6.
96. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, et al. Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 2010;116:2078-88.
97. Hoellenriegel J, Meadows SA, Sivina M, Wierda WG, Kantarjian H, Keating MJ, et al. The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood 2011;118:3603-12.
98. Ammirante M, Luo JL, Grivennikov S, Nedospasov S, Karin M. B-cellderived lymphotoxin promotes castration-resistant prostate cancer. Nature 2010;464:302-5.
99. Kerr WG, Colucci F. Inositol phospholipid signaling and the biology of natural killer cells. J Innate Immun 2011;3:249-57.
100. Zebedin E, Simma O, Schuster C, Putz EM, Fajmann S, Warsch W, et al. Leukemic challenge unmasks a requirement for PI3Kdelta in NK cell-mediated tumor surveillance. Blood 2008;112:4655-64.
101. Del Prete A, Vermi W, Dander E, Otero K, Barberis L, Luini W, et al. Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice. EMBO J 2004;23:3505-15.
102. Krishnamoorthy N, Oriss TB, Paglia M, Fei M, Yarlagadda M, Vanhaesebroeck B, et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat Med 2008;14:565-73.
103. Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, et al. Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J Cell Sci 2008;121:4124-33.
104. Kharas MG, Okabe R, Ganis JJ, Gozo M, Khandan T, Paktinat M, et al. Constitutively active AKT depletes hematopoietic stem cells and induces leukemia in mice. Blood 2010;115:1406-15.
105. 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;441:475-82.
106. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006;441:518-22.
107. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007;128:325-39.
108. Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, et al. AKT/FOXO Signaling Enforces Reversible Differentiation Blockade in Myeloid Leukemias. Cell 2011;146:697-708.