Skip to main content

The PI3 Kinase/Akt Pathway as a Therapeutic Target in Multiple Myeloma

  • Chapter
Myeloma Therapy

Part of the book series: Contemporary Hematology ((CH))

  • 567 Accesses

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lim, W.T., et al, PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. Oncol Rep, 2007. 17(4): 853–7.

    PubMed  CAS  Google Scholar 

  2. Bahlis, N.J., et al, CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood, 2007. 109(11): 5002–10.

    Article  PubMed  CAS  Google Scholar 

  3. Govindarajan, B., et al, Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J Clin Invest, 2007. 117(3): 719–29.

    Article  PubMed  CAS  Google Scholar 

  4. Meng, Q., et al, Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal, 2006. 18(12): 2262–71.

    Article  PubMed  CAS  Google Scholar 

  5. Opel, D., et al, Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res, 2007. 67(2): 735–45.

    Article  PubMed  CAS  Google Scholar 

  6. Tazzari, P.L., et al, Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia, 2007. 21(3): 427–38.

    Article  PubMed  CAS  Google Scholar 

  7. Tokunaga, E., et al, Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer, 2006. 13(2): 137–44.

    Article  PubMed  Google Scholar 

  8. Uddin, S., et al, Role of phosphatidylinositol 3″-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood, 2006. 108(13): 4178–86.

    Article  PubMed  CAS  Google Scholar 

  9. Cantrell, DA., Phosphoinositide 3-kinase signalling pathways. J Cell Sci, 2001. 114(Pt 8): 1439–45.

    PubMed  CAS  Google Scholar 

  10. Chang, F., et al, Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia, 2003. 17(3): 590–603.

    Article  PubMed  CAS  Google Scholar 

  11. Testa, J.R., et al and Bellacosa, A., AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA, 2001. 98(20): 10983–10985.

    Article  PubMed  CAS  Google Scholar 

  12. Carpten, J., et al, A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature, 2007. 448: 439–444.

    Article  PubMed  CAS  Google Scholar 

  13. Cheng, J.Q., Activation of the PI3K/Akt pathway and chemotherapeutic resistance. Drug Resist Update, 5: 131–146.

    Google Scholar 

  14. Arlt, A., et al, Role of NF- βB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death. Oncogene, 2003. 22: 3242–3251.

    Google Scholar 

  15. Kneufermann, C., et al, HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene, 2003. 22: 3205–3512.

    Article  Google Scholar 

  16. Yuan, Z.-Q., et al, AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: Implication of AKT2 in chemoresistance. J Biol Chem, 2003. 19: 2324–2330.

    Google Scholar 

  17. Nagata, Y., et al, PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell, 2004. 6: 117–127.

    Article  PubMed  CAS  Google Scholar 

  18. Athanassiadou, P., et al, The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: A prospective immunocytochemical study. Int J Gynecol Cancer, 2007. 17(3): 697–704.

    Article  PubMed  CAS  Google Scholar 

  19. Bepler, G., et al, RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. J Clin Oncol, 2004. 22(10): 1878–1885.

    Article  PubMed  CAS  Google Scholar 

  20. Edwards, L.A., et al, Inhibition of ILK in PTEN-mutant human glioblas-tomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene, 2005. 24(22): 3596–3605.

    Article  PubMed  CAS  Google Scholar 

  21. Ferraro, B., et al, EGR1 predicts PTEN and survival in patients with non-small-cell lung cancer. J Clin Oncol, 2005. 23(9): 1921–1926.

    Article  PubMed  CAS  Google Scholar 

  22. Schmitz, M., et al, Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer, 2007. 120(6): 1284–92.

    Article  PubMed  CAS  Google Scholar 

  23. Sui, L., et al, Alteration and clinical relevance of PTEN expression and its correlation with survivin expression in epithelial ovarian tumors. Oncol Rep, 2006. 15(4): 773–8.

    PubMed  CAS  Google Scholar 

  24. Tsutsui, S., et al, Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology, 2005. 68(4–6): 398–404.

    Article  PubMed  CAS  Google Scholar 

  25. Zhang, J., et al, Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene, 2003. 22(40): 6289–95.

    Article  PubMed  CAS  Google Scholar 

  26. Eng, C., PTEN: One gene, many syndromes. Hum Mutat, 2003. 22(3): 183–98.

    Article  PubMed  CAS  Google Scholar 

  27. Feng, Z., et al, The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res, 2007. 67(7): 3043–53.

    Article  PubMed  CAS  Google Scholar 

  28. Blanco-Aparicio, C., et al, PTEN, more than the AKT pathway. Carcinogenesis, 2007. 28(7): 1379–86.

    Article  PubMed  CAS  Google Scholar 

  29. Fruman, D.A., Meyers, R.E., and Cantley, L.C., Phosphoinositide kinases. Annu Rev Biochem, 1998. 67: 481–507.

    Article  PubMed  CAS  Google Scholar 

  30. Wymann, M.P., and Marone, R., Phosphoinositide 3-kinase in disease: Timing, location, and scaffolding. Current Opinion in Cell Biology, 2005. 17(2): 141–149.

    Article  PubMed  CAS  Google Scholar 

  31. Hunter, T., Signaling—2000 and beyond. Cell, 2000. 100(1): 113–27.

    Article  PubMed  CAS  Google Scholar 

  32. Datta, S.R., Brunet, A., and Greenberg, M.E., Cellular survival: a play in three Akts. Genes Dev, 1999. 13(22): 2905–27.

    Article  PubMed  CAS  Google Scholar 

  33. Hay, N., and Sonenberg, N., Upstream and downstream of mTOR. Genes Dev, 2004. 18(16): 1926–45.

    Article  PubMed  CAS  Google Scholar 

  34. Brunn, G.J., et al, 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(19): 5256–67.

    PubMed  CAS  Google Scholar 

  35. Cho, D., et al, The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res, 2007. 13(2 Pt 2): 758s–763s.

    Article  PubMed  CAS  Google Scholar 

  36. Smolewski, P., Recent developments in targeting the mammalian target of rapamy-cin (mTOR) kinase pathway. Anticancer Drugs, 2006. 17(5): 487–94.

    Article  PubMed  CAS  Google Scholar 

  37. Sun, S.Y., Fu, H., and Khuri, F.R., Targeting mTOR signaling for lung cancer therapy. J Thorac Oncol, 2006. 1(2): 109–11.

    Article  PubMed  Google Scholar 

  38. Sun, S.Y., et al, Activation of Akt and eIF4E survival pathways by rapamycin-medi-ated mammalian target of rapamycin inhibition. Cancer Res, 2005. 65(16): 7052–8.

    Article  PubMed  CAS  Google Scholar 

  39. Hay, N., The Akt-mTOR tango and its relevance to cancer. Cancer Cell, 2005. 8(3): 179–83.

    Article  PubMed  CAS  Google Scholar 

  40. Franke, T.F., et al, PI3K/Akt and apoptosis: Size matters. Oncogene, 2003. 22(56): 8983–98.

    Article  PubMed  CAS  Google Scholar 

  41. Downward, J., PI 3-kinase, Akt and cell survival. Semin Cell Dev Biol, 2004. 15(2): 177–82.

    Article  PubMed  CAS  Google Scholar 

  42. Liang, J., et al, PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med, 2002. 8(10): 1153–60.

    Article  PubMed  CAS  Google Scholar 

  43. Paik, J.H., et al, FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell, 2007. 128(2): 309–23.

    Article  PubMed  CAS  Google Scholar 

  44. Dong, X.Y., et al, FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res, 2006. 66(14): 6998–7006.

    Article  PubMed  CAS  Google Scholar 

  45. Mayo, L.D., and Donner, D.B., A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci U S A, 2001. 98(20): 11598–603.

    Article  PubMed  CAS  Google Scholar 

  46. Mayo, L.D., et al, PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy. J Biol Chem, 2002. 277(7): 5484–9.

    Article  PubMed  CAS  Google Scholar 

  47. Zhou, M., et al, PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res, 2003. 63(19): 6357–62.

    PubMed  CAS  Google Scholar 

  48. Hino, S., et al, Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol, 2005. 25(20): 9063–72.

    Article  PubMed  CAS  Google Scholar 

  49. Cross, D.A., et al, Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995. 378(6559): 785–9.

    Article  PubMed  CAS  Google Scholar 

  50. Workman, P., Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett, 2004. 206(2): 149–157.

    Article  PubMed  CAS  Google Scholar 

  51. Fujita, N., et al, Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J Biol Chem, 2002. 277(12): 10346–53.

    Article  PubMed  CAS  Google Scholar 

  52. Basso, A.D., et al, Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. Oncogene, 2002. 21(8): 1159–66.

    Article  PubMed  CAS  Google Scholar 

  53. Hideshima, T., et al, Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene, 2001. 20(42): 5991–6000.

    Article  PubMed  CAS  Google Scholar 

  54. Tu, Y., Gardner, A., and Lichtenstein, A., The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: Roles in cytokine-dependent survival and proliferative responses. Cancer Res, 2000. 60(23): 6763–70.

    PubMed  CAS  Google Scholar 

  55. Pene, F., et al, Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene, 2002. 21(43): 6587–97.

    Article  PubMed  CAS  Google Scholar 

  56. Yan, H., et al, Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res, 2006. 66(4): 2305–13.

    Article  PubMed  CAS  Google Scholar 

  57. Tai, Y.T., et al, CD40 induces human multiple myeloma cell migration via phosphati-dylinositol 3-kinase/AKT/NF-kappa B signaling. Blood, 2003. 101(7): 2762–9.

    Article  PubMed  CAS  Google Scholar 

  58. Descamps, G., et al, The magnitude of Akt/phosphatidylinositol 3″-kinase proliferating signaling is related to CD45 expression in human myeloma cells. J Immunol, 2004. 173(8): 4953–9.

    PubMed  CAS  Google Scholar 

  59. Gomez-Manzano, C., et al, Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann Neurol, 2003. 53(1): 109–17.

    Article  PubMed  CAS  Google Scholar 

  60. Saito, Y., et al, Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther, 2003. 10(11): 803–13.

    Article  PubMed  CAS  Google Scholar 

  61. Yi, H.-K., et al, Impact of PTEN on the expression of insulin-like growth factors (IGFs) and IGF-binding proteins in human gastric adenocarcinoma cells. Biochem Biophys Res Commun, 2005. 330(3): 760–767.

    Article  PubMed  CAS  Google Scholar 

  62. Hyun, T., et al, Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood, 2000. 96(10): 3560–8.

    PubMed  CAS  Google Scholar 

  63. Garlich, J., Development of a vascular targeted pan-PI3K inhibitor for cancer therapy. 3rd Focused Meeting on P13K signalling and disease Bath, UK 6–8 November 2006.

    Google Scholar 

  64. Bezieau, S., et al, High incidence of N and K-Ras activating mutations in multiple myeloma and primary plasma cell leukemia at diagnosis. Hum Mutat, 2001. 18: 212–242.

    Article  PubMed  CAS  Google Scholar 

  65. Liu, P., et al, Activating mutations of N and K-Ras in multiple myeloma show different clinical associations: Analysis of the Eastern Cooperative Oncology Group phase III trial. Blood, 1996. 88: 2699–2706.

    PubMed  CAS  Google Scholar 

  66. David, E., et al, The combination of farnesyl transferase inhibitor lonafarnib and the proteosome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT. Blood, 2005. 106: 4322–4329.

    Article  PubMed  CAS  Google Scholar 

  67. Zhu, K., Blood et al, 2005. 105: 4759–4766. Farnesyl transferase inhibitor R115777 (Zarnestra, Tipifarnib) synergizes with paclitaxel to induce apoptosis and mitotic arrest and to inhibit tumor growth of multiple myeloma cells.

    Google Scholar 

  68. Tai, Y.T., et al, Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood, 2007. 110: 1656–1663.

    Article  PubMed  CAS  Google Scholar 

  69. Hideshima, T., et al, Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood, 2003. 101: 703–705.

    Article  PubMed  CAS  Google Scholar 

  70. Hideshima, T., et al, p38 MAPK inhibition enhances PS-341 (bortezomib) induced cytotoxicity against multiple myeloma cells. Oncogene, 2004. 23: 8766–8776.

    Article  PubMed  CAS  Google Scholar 

  71. Wang, S., et al, Optimizing immunotherapy in multiple myeloma: Restoring the function of patients' monocyte derived dentritic cells by inhibiting p38 or activating MEK/ERK/MAPK and neutralizing IL-6 in progenitor cells. Blood, 2006. 108: 4071–4077.

    Article  PubMed  CAS  Google Scholar 

  72. Garlich, J.R., et al, A vascular targeted pan phosphoinositide 3-kinase inhibitor prodng, SF1126, with antitumor and antiangiogenic activity. Cancer Res, 2008 68(1): 206–15.

    Article  PubMed  CAS  Google Scholar 

  73. Ruiter, G.A., et al, Anti-cancer alkyl-lysophospholipids inhibit the phosphati-dylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs, 2003. 14(2): 167–73.

    Article  PubMed  CAS  Google Scholar 

  74. Giuliani, N., et al, Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. Leukemia, 2004. 18(3): 628–35.

    Article  PubMed  CAS  Google Scholar 

  75. Ihle, N.T., et al, Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther, 2004. 3(7): 763–72.

    PubMed  CAS  Google Scholar 

  76. Ohta, T., et al, Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology, 2006. 147(4): 1761–9.

    Article  PubMed  CAS  Google Scholar 

  77. Fujiwara, Y., et al, Blockade of the phosphatidylinositol-3-kinase-Akt signaling pathway enhances the induction of apoptosis by microtubule-destabilizing agents in tumor cells in which the pathway is constitutively activated. Mol Cancer Ther, 2007. 6(3): 1133–42.

    Article  PubMed  CAS  Google Scholar 

  78. Catley, L., et al, Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp Hematol, 2007. 35(7): 1038–46.

    Article  PubMed  CAS  Google Scholar 

  79. Gajate, C., and Mollinedo, F., Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood, 2007. 109(2): 711–9.

    Article  PubMed  CAS  Google Scholar 

  80. Hideshima, T., et al, Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 2006. 107(10): 4053–62.

    Article  PubMed  CAS  Google Scholar 

  81. Richardson, P., et al, A Multicenter Phase II Study of perifosine (KRX-0401) alone and in combination with dexamethasone (Dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM). ASH Annual Meeting Abstracts, 2006. 108(11): Abstract 3582.

    Google Scholar 

  82. Dees, E.C., et al, A phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin Cancer Res, 2005. 11(2 Pt 1): 664–71.

    PubMed  CAS  Google Scholar 

  83. Sausville, E.A., et al, Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J Clin Oncol, 2001. 19(8): 2319–33.

    PubMed  CAS  Google Scholar 

  84. Dai, Y., Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood, 2007. 109(10): 4415–23.

    Article  PubMed  CAS  Google Scholar 

  85. Jiang, K., et al, The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol Cell Biol, 2000. 20(1): 139–48.

    Article  PubMed  Google Scholar 

  86. Yanamandra, N., et al, Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid leukemia. Clin Cancer Res, 2006. 12(2): 591–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Harvey, R.D., Silberman, J., Lonial, S. (2008). The PI3 Kinase/Akt Pathway as a Therapeutic Target in Multiple Myeloma. In: Lonial, S. (eds) Myeloma Therapy. Contemporary Hematology. Humana Press. https://doi.org/10.1007/978-1-59745-564-0_20

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-564-0_20

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-934115-82-4

  • Online ISBN: 978-1-59745-564-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics