The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eμ-TCL1 mouse model

Blood

Volumn 125, Issue 26, 2015, Pages 4032-4041

  Blunt, Matthew D ^a   Carter, Matthew J ^a   Larrayoz, Marta ^a   Smith, Lindsay D ^a   Aguilar Hernandez, Maria ^a,b   Cox, Kerry L ^a   Tipton, Thomas ^a   Reynolds, Mark ^a   Murphy, Sarah ^a   Lemm, Elizabeth ^a   Dias, Samantha ^a   Duncombe, Andrew ^a,c   Strefford, Jonathan C ^a   Johnson, Peter W M ^a   Forconi, Francesco ^a,c,d   Stevenson, Freda K ^a   Packham, Graham ^a   Cragg, Mark S ^a   Steele, Andrew J ^a  

^a UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^b INSTITUTO NACIONAL DE PEDIATRÍA   (Mexico)

^c SOUTHAMPTON GENERAL HOSPITAL   (United Kingdom)

^d UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 8 [4 (2 HYDROXYETHOXY)CYCLOHEXYL] 6 (6 METHOXY 3 PYRIDINYL) 4 METHYLPYRIDO[2,3 D]PYRIMIDIN 7(8H) ONE; CHEMOKINE RECEPTOR CXCR4; IMMUNOGLOBULIN HEAVY CHAIN; PROTEIN NOXA; PUMA PROTEIN; 2-AMINO-8-(4-(2-HYDROXYETHOXY)CYCLOHEXYL)-6-(6-METHOXYPYRIDIN-3-YL)-4-METHYLPYRIDO(2,3-D)PYRIMIDIN-7(8H)-ONE; ANTINEOPLASTIC AGENT; MTOR PROTEIN, HUMAN; PHOSPHATIDYLINOSITOL 3 KINASE; PYRIDONE DERIVATIVE; PYRIMIDINE DERIVATIVE; TARGET OF RAPAMYCIN KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CELL MIGRATION; CELL SURVIVAL; CELL VIABILITY; CHRONIC LYMPHATIC LEUKEMIA; CONTROLLED STUDY; HUMAN; HUMAN CELL; LYMPHOCYTOSIS; MOUSE; MOUSE MODEL; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT; ANIMAL; ANTAGONISTS AND INHIBITORS; C57BL MOUSE; CELL CULTURE; DISEASE MODEL; DRUG EFFECTS; FEMALE; METABOLISM; PATHOLOGY; WESTERN BLOTTING;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BLOTTING, WESTERN; CELLS, CULTURED; DISEASE MODELS, ANIMAL; FEMALE; HUMANS; LEUKEMIA, LYMPHOCYTIC, CHRONIC, B-CELL; MICE; MICE, INBRED C57BL; PHOSPHATIDYLINOSITOL 3-KINASES; PYRIDONES; PYRIMIDINES; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84933564564     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2014-11-610329     Document Type: Article

References (51)

1. Kay NE, O'Brien SM, Pettitt AR, Stilgenbauer S. The role of prognostic factors in assessing 'high-risk' subgroups of patients with chronic lymphocytic leukemia. Leukemia. 2007;21(9):1885-1891.
2. Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol. 2013;88(9):803-816.
3. Pleyer L, Egle A, Hartmann TN, Greil R. Molecular and cellular mechanisms of CLL: novel therapeutic approaches. Nat Rev Clin Oncol. 2009;6(7):405-418.
4. Markham A. Idelalisib: first global approval. Drugs. 2014;74(14):1701-1707.
5. Cameron F, Sanford M. Ibrutinib: first global approval. Drugs. 2014;74(2):263-271.
6. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110d, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
7. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
8. Davids MS, Brown JR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma. 2012;53(12):2362-2370.
9. Byrd JC, Brown JR, O'Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
10. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
11. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578-2585.
12. Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin Cancer Biol. 2014;24:71-81.
13. Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013;31:675-704.
14. Kulkarni S, Sitaru C, Jakus Z, et al. PI3Kb plays a critical role in neutrophil activation by immune complexes. Sci Signal. 2011;4(168):ra23.
15. Juss JK, Hayhoe RP, Owen CE, et al. Functional redundancy of class I phosphoinositide 3-kinase (PI3K) isoforms in signaling growth factor-mediated human neutrophil survival. PLoS ONE. 2012;7(9):e45933.
16. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell. 2012;149(2):274-293.
17. Ringshausen I, Schneller F, Bogner C, et al. Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cdelta. Blood. 2002;100(10):3741-3748.
18. Kienle D, Benner A, Kröber A, et al. Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes. Blood. 2006;107(5):2090-2093.
19. Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-d inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088.
20. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 39-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118(13):3603-3612.
21. Lannutti BJ, Meadows SA, Herman SE, 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):591-594.
22. de Frias M, Iglesias-Serret D, Cosialls AM, et al. Isoform-selective phosphoinositide 3-kinase inhibitors induce apoptosis in chronic lymphocytic leukaemia cells. Br J Haematol. 2010;150(1):108-111.
23. Niedermeier M, Hennessy BT, Knight ZA, et al. Isoform-selective phosphoinositide 39-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009;113(22):5549-5557.
24. Decker T, Hipp S, Ringshausen I, et al. Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood. 2003;101(1):278-285.
25. Hayun R, Okun E, Berrebi A, et al. Rapamycin and curcumin induce apoptosis in primary resting B chronic lymphocytic leukemia cells. Leuk Lymphoma. 2009;50(4):625-632.
26. Aleskog A, Norberg M, Nygren P, et al. Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination. Leuk Lymphoma. 2008;49(12):2333-2343.
27. O'Reilly KE, Rojo F, She QB, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66(3):1500-1508.
28. Tamburini J, Chapuis N, Bardet V, et al. Mammalian target of rapamycin (mTOR) inhibition activates phosphatidylinositol 3-kinase/Akt by upregulating insulin-like growth factor-1 receptor signaling in acute myeloid leukemia: rationale for therapeutic inhibition of both pathways. Blood. 2008;111(1):379-382.
29. Yuan J, Mehta PP, Yin MJ, et al. PF-04691502, a potent and selective oral inhibitor of PI3K and mTOR kinases with antitumor activity. Mol Cancer Ther. 2011;10(11):2189-2199.
30. Wong CH, Loong HH, Hui CW, et al. Preclinical evaluation of the PI3K-mTOR dual inhibitor PF-04691502 as a novel therapeutic drug in nasopharyngeal carcinoma. Invest New Drugs. 2013;31(6):1399-1408.
31. Fang DD, Zhang CC, Gu Y, et al. Antitumor efficacy of the dual PI3K/mTOR inhibitor PF-04691502 in a human xenograft tumor model derived from colorectal cancer stem cells harboring a PIK3CA mutation. PLoS ONE. 2013;8(6):e67258.
32. Simmons BH, Lee JH, Lalwani K, et al. Combination of a MEK inhibitor at sub-MTD with a PI3K/mTOR inhibitor significantly suppresses growth of lung adenocarcinoma tumors in Kras (G12D-LSL) mice. Cancer Chemother Pharmacol. 2012;70(2):213-220.
33. Wang FZ, Peng-Jiao, Yang NN, et al. PF-04691502 triggers cell cycle arrest, apoptosis and inhibits the angiogenesis in hepatocellular carcinoma cells. Toxicol Lett. 2013;220(2):150-156.
34. Britten CD, Adjei AA, Millham R, et al. Phase I study of PF-04691502, a small-molecule, oral, dual inhibitor of PI3K and mTOR, in patients with advanced cancer. Invest New Drugs. 2014;32(3):510-517.
35. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
36. Mockridge CI, Potter KN, Wheatley I, Neville LA, Packham G, Stevenson FK. Reversible anergy of sIgM-mediated signaling in the two subsets of CLL defined by VH-gene mutational status. Blood. 2007;109(10):4424-4431.
37. Steele AJ, Prentice AG, Hoffbrand AV, et al. 2-Phenylacetylenesulfonamide (PAS) induces p53-independent apoptotic killing of B-chronic lymphocytic leukemia (CLL) cells. Blood. 2009;114(6):1217-1225.
38. Steele AJ, Prentice AG, Hoffbrand AV, et al. p53-mediated apoptosis of CLL cells: evidence for a transcription-independent mechanism. Blood. 2008;112(9):3827-3834.
39. Steele AJ, Prentice AG, Cwynarski K, et al. The JAK3-selective inhibitor PF-956980 reverses the resistance to cytotoxic agents induced by interleukin-4 treatment of chronic lymphocytic leukemia cells: potential for reversal of cytoprotection by the microenvironment. Blood. 2010;116(22):4569-4577.
40. Stevenson FK, Krysov S, Davies AJ, Steele AJ, Packham G. B-cell receptor signaling in chronic lymphocytic leukemia. Blood. 2011;118(16):4313-4320.
41. Krysov S, Steele AJ, Coelho V, et al. Stimulation of surface IgM of chronic lymphocytic leukemia cells induces an unfolded protein response dependent on BTK and SYK. Blood. 2014;124(20):3101-3109.
42. Herman SE, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287-6296.
43. Iyengar S, Clear A, Bödör C, et al. P110amediated constitutive PI3K signaling limits the efficacy of p110d-selective inhibition in mantle cell lymphoma, particularly with multiple relapse. Blood. 2013;121(12):2274-2284.
44. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124(24):3583-3586.
45. Amrein L, Shawi M, Grenier J, Aloyz R, Panasci L. The phosphatidylinositol-3 kinase I inhibitor BKM120 induces cell death in B-chronic lymphocytic leukemia cells in vitro. Int J Cancer. 2013;133(1):247-252.
46. Foster JG, Blunt MD, Carter E, Ward SG. Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol Rev. 2012;64(4):1027-1054.
47. Foukas LC, Bilanges B, Bettedi L, et al. Long-term p110a PI3K inactivation exerts a beneficial effect on metabolism. EMBO Mol Med. 2013;5(4):563-571.
48. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117(2):563-574.
49. Burger JA, Tsukada N, Burger M, Zvaifler NJ, Dell'Aquila M, Kipps TJ. Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cellderived factor-1. Blood. 2000;96(8):2655-2663.
50. Wodarz D, Garg N, Komarova NL, et al. Kinetics of CLL cells in tissues and blood during therapy with the BTK inhibitor ibrutinib. Blood. 2014;123(26):4132-4135.
51. Smit LA, Hallaert DY, Spijker R, et al. Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. Blood. 2007;109(4):1660-1668.