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Regenerative Medicine

PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma

    R Donald Harvey

    † Author for correspondence

    Emory University School of Medicine, Winship Cancer Institute, 1365 C Clifton Road, Atlanta, GA 30322, USA.

    &
    Sagar Lonial

    Emory University School of Medicine, Winship Cancer Institute, 1365 C Clifton Road, Atlanta, GA 30322, USA.

    Published Online:https://doi.org/10.2217/14796694.3.6.639

    The development of novel therapies for multiple myeloma depends on a comprehensive understanding of the events leading to cellular proliferation and survival. Controlling pathways that regulate growth signals is an emerging and complementary approach to myeloma treatment. The PI3K/Akt pathway is a central gatekeeper for crucial cellular functions including adhesion, angiogenesis, migration and development of drug resistance. Established proteins and genes such as mTOR, p53, NF-κB and BAD are all regulated through PI3K and Akt activation, making them attractive targets for broad downstream effects. Direct PI3K inhibition has demonstrated impressive tumor inhibition and regression in cell-line and animal models, and multiple agents including SF1126 are currently in clinical trials. Drugs such as perifosine that are specific for Akt are also in development. Combinations of these agents with existing therapies are rational approaches on the path to improving myeloma treatment.

    Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

    Bibliography

    • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ: Cancer Statistics, 2007. CA Cancer J. Clin.57(1),43–66 (2007).
    • Dispenzieri A, Rajkumar SV, Gertz MA et al.: Treatment of newly diagnosed multiple myeloma based on Mayo Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo. Clin. Proc.82(3),323–341 (2007).
    • Lim WT, Zhang WH, Miller CR et al.: PTEN and phosphorylated AKT expression and prognosis in early- and late-stage non-small cell lung cancer. Oncol. Rep.17(4),853–857 (2007).
    • Bahlis NJ, King AM, Kolonias D et al.: CD28-mediated regulation of multiple myeloma cell proliferation and survival. Blood109(11),5002–5010 (2007).
    • Govindarajan B, Sligh JE, Vincent BJ et al.: Overexpression of Akt converts radial growth melanoma to vertical growth melanoma. J. Clin. Invest.117(3),719–729 (2007).
    • Meng Q, Xia C, Fang J, Rojanasakul Y, Jiang BH: Role of PI3K and AKT specific isoforms in ovarian cancer cell migration, invasion and proliferation through the p70S6K1 pathway. Cell Signal.18(12),2262–2271 (2006).
    • Opel D, Poremba C, Simon T, Debatin KM, Fulda S: Activation of Akt predicts poor outcome in neuroblastoma. Cancer Res.67(2),735–745 (2007).
    • Tazzari PL, Cappellini A, Ricci F 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. Leukemia21(3),427–438 (2007).
    • Tokunaga E, Kimura Y, Mashino K et al.: Activation of PI3K/Akt signaling and hormone resistance in breast cancer. Breast Cancer13(2),137–144 (2006).
    • 10  Uddin S, Hussain AR, Siraj AK et al.: Role of phosphatidylinositol 3'-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood108(13),4178–4186 (2006).
    • 11  Cantrell DA: Phosphoinositide 3-kinase signalling pathways. J. Cell Sci.114(Pt 8),1439–1445 (2001).
    • 12  Chang F, Lee JT, Navolanic PM et al.: Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia17(3),590–603 (2003).
    • 13  Athanassiadou P, Athanassiades P, Grapsa D et al.: The prognostic value of PTEN, p53, and beta-catenin in endometrial carcinoma: a prospective immunocytochemical study. Int. J. Gynecol. Cancer17(3),697–704 (2007).
    • 14  Bepler G, Sharma S, Cantor A 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.22(10),1878–1885 (2004).
    • 15  Edwards LA, Thiessen B, Dragowska WH, Daynard T, Bally MB, Dedhar S: Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB//Akt activation, induces apoptosis, and delays tumor growth. Oncogene24(22),3596–3605 (2005).
    • 16  Ferraro B, Bepler G, Sharma S, Cantor A, Haura EB: EGR1 Predicts PTEN and survival in patients with non-small-cell lung cancer. J. Clin. Oncol.23(9),1921–1926 (2005).
    • 17  Schmitz M, Grignard G, Margue C et al.: Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int. J. Cancer120(6),1284–1292 (2007).
    • 18  Sui L, Dong Y, Watanabe Y, Yamaguchi F, Sugimoto K, Tokuda M: Alteration and clinical relevance of PTEN expression and its correlation with survivin expression in epithelial ovarian tumors. Oncol. Rep.15(4),773–778 (2006).
    • 19  Tsutsui S, Inoue H, Yasuda K et al.: Reduced expression of PTEN protein and its prognostic implications in invasive ductal carcinoma of the breast. Oncology68(4–6),398–404 (2005).
    • 20  Chang H, Qi XY, Claudio J, Zhuang L, Patterson B, Stewart AK: Analysis of PTEN deletions and mutations in multiple myeloma. Leuk. Res.30(3),262–265 (2006).• The authors describe the first series of patients with advanced myeloma and define PTEN loss and mutation status.
    • 21  Eng C: PTEN: one gene, many syndromes. Hum. Mutat.22(3),183–198 (2003).
    • 22  Feng Z, Hu W, de Stanchina E 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.67(7),3043–3053 (2007).
    • 23  Blanco-Aparicio C, Renner O, Leal JF, Carnero A: PTEN, more than the AKT pathway. Carcinogenesis28(7),1379–1386 (2007).
    • 24  Fruman DA, Meyers RE, Cantley LC: Phosphoinositide kinases. Annu. Rev. Biochem.67,481–507 (1998).
    • 25  Wymann MP, Marone R: Phosphoinositide 3-kinase in disease: timing, location, and scaffolding. Curr. Opin. Cell Biol.17(2),141–149 (2005).
    • 26  Cully M, You H, Levine AJ, Mak TW: Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer6(3),184–192 (2006).•• Excellent discussion of the complexity of the PI3K/Akt pathway and challenges in drug development.
    • 27  Datta SR, Brunet A, Greenberg ME: Cellular survival: a play in three Akts. Genes Dev.13(22),2905–2927 (1999).
    • 28  Alessi DR, Andjelkovic M, Caudwell B et al.: Mechanism of activation of protein kinase B by insulin and IGF-1. Embo. J.15(23),6541–6551 (1996).•• Description of the discovery that independent phosphorylation at two distinct sites is required for Akt activity.
    • 29  Jacinto E, Facchinetti V, Liu D et al.: SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell127(1),125–137 (2006).
    • 30  Hay N, Sonenberg N: Upstream and downstream of mTOR. Genes Dev.18(16),1926–1945 (2004).
    • 31  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.15(19),5256–5267 (1996).
    • 32  Cho D, Signoretti S, Regan M, Mier JW, Atkins MB: The role of mammalian target of rapamycin inhibitors in the treatment of advanced renal cancer. Clin Cancer Res.13(2 Pt 2),758S–763S (2007).
    • 33  Smolewski P: Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway. Anticancer Drugs17(5),487–494 (2006).
    • 34  Sun SY, Fu H, Khuri FRL: Targeting mTOR signaling for lung cancer therapy. J. Thorac. Oncol.1(2),109–111 (2006).
    • 35  Sun SY, Rosenberg LM, Wang X et al.: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res.65(16),7052–7058 (2005).
    • 36  Hay N: The Akt-mTOR tango and its relevance to cancer. Cancer Cell8(3),179–183 (2005).
    • 37  Franke TF, Hornik CP, Segev L, Shostak GA, Sugimoto C: PI3K/Akt and apoptosis: size matters. Oncogene22(56),8983–8998 (2003).
    • 38  Downward J: PI 3-kinase, Akt and cell survival. Semin. Cell Dev. Biol.15(2),177–182 (2004).
    • 39  Liang J, Zubovitz J, Petrocelli T et al.: PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat. Med.8(10),1153–1160 (2002).
    • 40  Paik JH, Kollipara R, Chu G et al.: FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell128(2),309–323 (2007).
    • 41  Dong XY, Chen C, Sun X et al.: FOXO1A is a candidate for the 13q14 tumor suppressor gene inhibiting androgen receptor signaling in prostate cancer. Cancer Res.66(14),6998–7006 (2006).
    • 42  Mayo LD, Donner DB: A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA98(20),11598–11603 (2001).
    • 43  Li AG, Piluso LG, Cai X, Wei G, Sellers WR, Liu X et al.: Mechanistic insights into maintenance of high p53 acetylation by PTEN. Molecular Cell23(4),575–587 (2006).• First description of the ability of PTEN to migrate into the nucleus and promote p53 survival.
    • 44  Hino S, Tanji C, Nakayama KI, Kikuchi A: Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes β-catenin through inhibition of its ubiquitination. Mol. Cell Biol.25(20),9063–9072 (2005).
    • 45  Karim R, Tse G, Putti T, Scolyer R, Lee S: The significance of the Wnt pathway in the pathology of human cancers. Pathology36(2),120–128 (2004).
    • 46  Inoki K, Ouyang H, Zhu T et al.: TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell126(5),955–968 (2006).
    • 47  Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature378(6559),785–789 (1995).
    • 48  Workman P: Combinatorial attack on multistep oncogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Letters206(2),149–157 (2004).
    • 49  Fujita N, Sato S, Ishida A, Tsuruo T: Involvement of Hsp90 in signaling and stability of 3-phosphoinositide-dependent kinase-1. J. Biol. Chem.277(12),10346–10353 (2002).
    • 50  Basso AD, Solit DB, Munster PN, Rosen N: Ansamycin antibiotics inhibit Akt activation and cyclin D expression in cells that overexpress HER2. Oncogene21(8),1159–1166 (2002).
    • 51  Zhang J, Choi Y, Mavromatis B, Lichtenstein A, Li W: Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene22(40),6289–6295 (2003).
    • 52  Tai YT, Podar K, Mitsiades N et al.: CD40 induces human multiple myeloma cell migration via phosphatidylinositol 3-kinase/AKT/NF-kappa B signaling. Blood101(7),2762–2769 (2003).
    • 53  Descamps G, Pellat-Deceunynck C, Szpak Y, Bataille R, Robillard N, Amiot M: The magnitude of Akt/phosphatidylinositol 3´-kinase proliferating signaling is related to CD45 expression in human myeloma cells. J. Immunol.173(8),4953–4959 (2004).
    • 54  Hsu JH, Shi Y, Frost P et al.: Interleukin-6 activates phosphoinositol-3´ kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. Oncogene23(19),3368–3375 (2004).
    • 55  Hideshima T, Nakamura N, Chauhan D, Anderson KC: Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene20(42),5991–6000 (2001).•• Demonstrates the interdependence between IL-6 and the PI3K/Akt pathway in dexamethasone-resistant myeloma.
    • 56  Tu Y, Gardner A, Lichtenstein A: The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res.60(23),6763–6770 (2000).
    • 57  Hu L, Shi Y, Hsu JH, Gera J, Van Ness B, Lichtenstein A: Downstream effectors of oncogenic ras in multiple myeloma cells. Blood101(8),3126–3135 (2003).
    • 58  Pene F, Claessens YE, Muller O et al.: Role of the phosphatidylinositol 3-kinase/Akt and mTOR/P70S6-kinase pathways in the proliferation and apoptosis in multiple myeloma. Oncogene21(43),6587–6597 (2002).
    • 59  Yan H, Frost P, Shi Y et al.: Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res.66(4),2305–2313 (2006).
    • 60  Frost P, Shi Y, Hoang B, Lichtenstein A: AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene26(16),2255–2262 (2007).•• Report of mTOR inhibition leading to reduced angiogenesis through Akt stimulation.
    • 61  Mirshahi P, Toprak SK, Faussat AM et al.: Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signalling pathways. Biochem. Biophys. Res. Commun.349(3),1003–1010 (2006).
    • 62  Shi Y, Yan H, Frost P, Gera J, Lichtenstein A: Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol. Cancer Ther.4(10),1533–1540 (2005).
    • 63  Bergsagel PL, Kuehl WM, Zhan F, Sawyer J, Barlogie B, Shaughnessy J Jr : Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood106(1),296–303 (2005).
    • 64  Bergsagel PL, Kuehl WM: Molecular pathogenesis and a consequent classification of multiple myeloma. J. Clin. Oncol.23(26),6333–6338 (2005).
    • 65  Ikezoe T, Nishioka C, Bandobashi K et al.: Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell Leukemia cells. Leuk. Res.31(5),673–682 (2007).
    • 66  Mitsiades CS, Mitsiades NS, McMullan CJ et al.: Antimyeloma activity of heat shock protein-90 inhibition. Blood107(3),1092–1100 (2006).
    • 67  Gomez-Manzano C, Fueyo J, Jiang H et al.: Mechanisms underlying PTEN regulation of vascular endothelial growth factor and angiogenesis. Ann. Neurol.53(1),109–117 (2003).
    • 68  Saito Y, Gopalan B, Mhashilkar AM et al.: Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells. Cancer Gene Ther.10(11),803–813 (2003).
    • 69  Yi HK, Kim SY, Hwang PH 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.330(3),760–767 (2005).
    • 70  Hyun T, Yam A, Pece S et al.: Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood96(10),3560–3568 (2000).
    • 71  Garlich J: Development of a vascular targeted pan-PI3K inhibitor for cancer therapy. 3rd Focused Meeting on PI3K signalling and disease. Bath, UK 6–8 November 2006.
    • 72  Pradip D, Peng Q, Dey N et al.: A vascular targeted pan PI-3 kinase inhibitor, SF1126 with activity against multiple myeloma in vivo. ASH Annual Meeting Abstracts. Blood108(11) (2006) (Abstract 244).
    • 73  Ruiter GA, Zerp SF, Bartelink H, van Blitterswijk WJ, Verheij M: Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs14(2),167–173 (2003).
    • 74  Giuliani N, Lunghi P, Morandi F et al.: Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis. Leukemia18(3),628–635 (2004).
    • 75  Ihle NT, Williams R, Chow S et al.: Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol. Cancer Ther.3(7),763–772 (2004).
    • 76  Ohta T, Ohmichi M, Hayasaka T et al.: Inhibition of phosphatidylinositol 3-kinase increases efficacy of cisplatin in in vivo ovarian cancer models. Endocrinology147(4),1761–1769 (2006).
    • 77  Fujiwara Y, Hosokawa Y, Watanabe K, Tanimura S, Ozaki K, Kohno M: 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.6(3),1133–1142 (2007).
    • 78  Catley L, Hideshima T, Chauhan D et al.: Alkyl phospholipid perifosine induces myeloid hyperplasia in a murine myeloma model. Exp. Hematol.35(7),1038–1046 (2007).
    • 79  Gajate C, Mollinedo F: Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood109(2),711–719 (2007).
    • 80  Hideshima T, Catley L, Yasui H et al.: Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood107(10),4053–4062 (2006).
    • 81  Richardson P, Lonial S, Jakubowiak A 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.Blood108(11) (2006) (Abstract 3582).
    • 82  Dees EC, Baker SD, O’Reilly S et al.: A Phase I and pharmacokinetic study of short infusions of UCN-01 in patients with refractory solid tumors. Clin. Cancer Res.11(2 Pt 1),664–671 (2005).
    • 83  Sausville EA, Arbuck SG, Messmann R et al.: Phase I trial of 72-hour continuous infusion UCN-01 in patients with refractory neoplasms. J. Clin. Oncol.19(8),2319–2333 (2001).
    • 84  Dai Y, Khanna P, Chen S, Pei XY, Dent P, Grant S: Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human Leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood109(10),4415–4423 (2007).
    • 85  Jiang K, Coppola D, Crespo NC et al.: The phosphoinositide 3-OH kinase/ AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell Biol.20(1),139–148 (2000).
    • 86  Yanamandra N, Colaco NM, Parquet NA et al.: Tipifarnib and bortezomib are synergistic and overcome cell adhesion-mediated drug resistance in multiple myeloma and acute myeloid Leukemia. Clin Cancer Res.12(2),591–599 (2006).