PI3K/AKT/mTOR pathway in multiple myeloma: from basic biology to clinical promise

References

• Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412–5417.
   PubMed Web of Science ®Google Scholar
• Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564–569.
   PubMed Web of Science ®Google Scholar
• Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362–1369.
   PubMed Web of Science ®Google Scholar
• Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582–2590.
   PubMed Web of Science ®Google Scholar
• Fonseca R, Bailey RJ, Ahmann GJ, et al. Genomic abnormalities in monoclonal gammopathy of undetermined significance. Blood. 2002;100:1417–1424.
   PubMed Web of Science ®Google Scholar
• Avet-Loiseau H, Facon T, Grosbois B, et al. Oncogenesis of multiple myeloma: 14q32 and 13q chromosomal abnormalities are not randomly distributed, but correlate with natural history, immunological features, and clinical presentation. Blood. 2002;99:2185–2191.
   PubMed Web of Science ®Google Scholar
• Avet-Loiseau H, Facon T, Daviet A, et al. 14q32 translocations and monosomy 13 observed in monoclonal gammopathy of undetermined significance delineate a multistep process for the oncogenesis of multiple myeloma. Intergroupe Francophone du Myelome. Cancer Res. 1999;59:4546–4550.
   PubMed Web of Science ®Google Scholar
• Dhodapkar MV, Sexton R, Waheed S, et al. Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood. 2014;123:78–85.
   PubMed Web of Science ®Google Scholar
• Rajkumar SV, Gupta V, Fonseca R, et al. Impact of primary molecular cytogenetic abnormalities and risk of progression in smoldering multiple myeloma. Leukemia. 2013;27:1738–1744.
   PubMed Web of Science ®Google Scholar
• Keats JJ, Reiman T, Maxwell CA, et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003;101:1520–1529.
   PubMed Web of Science ®Google Scholar
• Chng WJ, Gonzalez-Paz N, Price-Troska T, et al. Clinical and biological significance of RAS mutations in multiple myeloma. Leukemia. 2008;22:2280–2284.
   PubMed Web of Science ®Google Scholar
• Chng WJ, Huang GF, Chung TH, et al. Clinical and biological implications of MYC activation: a common difference between MGUS and newly diagnosed multiple myeloma. Leukemia. 2011;25:1026–1035.
   PubMed Web of Science ®Google Scholar
• Chapman MA, Lawrence MS, Keats JJ, et al. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471:467–472.
   PubMed Web of Science ®Google Scholar
• Lohr JG, Stojanov P, Carter SL, et al. Widespread genetic heterogeneity in multiple myeloma: implications for targeted therapy. Cancer Cell. 2014;25:91–101.
   PubMed Web of Science ®Google Scholar
• Keats JJ, Fonseca R, Chesi M, et al. Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell. 2007;12:131–144.
   PubMed Web of Science ®Google Scholar
• Kortum KM, Mai EK, Hanafiah NH, et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood. 2016;128:1226–1233.
   PubMed Web of Science ®Google Scholar
• Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122–1128.
   PubMed Web of Science ®Google Scholar
• Di Marzo L, Desantis V, Solimando AG, et al. Microenvironment drug resistance in multiple myeloma: emerging new players. Oncotarget. 2016;7:60698–60711.
   PubMed Web of Science ®Google Scholar
• Hideshima T, Mitsiades C, Tonon G, et al. Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nat Rev Cancer. 2007;7:585–598.
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–976.
   PubMed Web of Science ®Google Scholar
• Mayer IA, Arteaga CL. The PI3K/AKT pathway as a target for cancer treatment. Annu Rev Med. 2016;67:11–28.
   PubMed Web of Science ®Google Scholar
• Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov. 2014;13:140–156.
   PubMed Web of Science ®Google Scholar
• Ismail SI, Mahmoud IS, Msallam MM, et al. Hotspot mutations of PIK3CA and AKT1 genes are absent in multiple myeloma. Leuk Res. 2010;34:824–826.
   PubMed Web of Science ®Google Scholar
• Chang H, Qi XY, Claudio J, et al. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res. 2006;30:262–265.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, D’Souza A. Signaling pathways and emerging therapies in multiple myeloma. Curr Hematol Malig Rep. 2016;11:156–164.
   PubMed Web of Science ®Google Scholar
• Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–1274.
   PubMed Web of Science ®Google Scholar
• Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer. 2002;2:489–501.
   PubMed Web of Science ®Google Scholar
• Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002;110:163–175.
   PubMed Web of Science ®Google Scholar
• Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110:177–189.
   PubMed Web of Science ®Google Scholar
• Kim DH, Sarbassov DD, Ali SM, et al. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003;11:895–904.
   PubMed Web of Science ®Google Scholar
• Sancak Y, Thoreen CC, Peterson TR, et al. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007;25:903–915.
   PubMed Web of Science ®Google Scholar
• Wang L, Harris TE, Roth RA, et al. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem. 2007;282:20036–20044., Jr.
   PubMed Web of Science ®Google Scholar
• Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell. 2009;137:873–886.
   PubMed Web of Science ®Google Scholar
• Jacinto E, Loewith R, Schmidt A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122–1128.
   PubMed Web of Science ®Google Scholar
• Frias MA, Thoreen CC, Jaffe JD, et al. mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2s. Curr Biol. 2006;16:1865–1870.
   PubMed Web of Science ®Google Scholar
• Pearce LR, Huang X, Boudeau J, et al. Identification of Protor as a novel Rictor-binding component of mTOR complex-2. Biochem J. 2007;405:513–522.
   PubMed Web of Science ®Google Scholar
• Bracho-Valdes I, Moreno-Alvarez P, Valencia-Martinez I, et al. mTORC1- and mTORC2-interacting proteins keep their multifunctional partners focused. IUBMB Life. 2011;63:896–914.
   PubMed Web of Science ®Google Scholar
• Fernandez-Saiz V, Targosz BS, Lemeer S, et al. SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma. Nat Cell Biol. 2013;15:72–81.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Gomez M, Prasad V, et al. Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma. Oncotarget. 2016;7:56253–56265.
   PubMed Web of Science ®Google Scholar
• Du J, Liu S, He J, et al. MicroRNA-451 regulates stemness of side population cells via PI3K/Akt/mTOR signaling pathway in multiple myeloma. Oncotarget. 2015;6:14993–15007.
   PubMed Web of Science ®Google Scholar
• Yu CF, Liu ZX, Cantley LG. ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. J Biol Chem. 2002;277:19382–19388.
   PubMed Web of Science ®Google Scholar
• Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999;286:1741–1744.
   PubMed Web of Science ®Google Scholar
• Guan KL, Figueroa C, Brtva TR, et al. Negative regulation of the serine/threonine kinase B-Raf by Akt. J Biol Chem. 2000;275:27354–27359.
   PubMed Web of Science ®Google Scholar
• Kodaki T, Woscholski R, Hallberg B, et al. The activation of phosphatidylinositol 3-kinase by Ras. Curr Biol. 1994;4:798–806.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Viciana P, Warne PH, Dhand R, et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994;370:527–532.
   PubMed Web of Science ®Google Scholar
• Roux PP, Ballif BA, Anjum R, et al. Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc Natl Acad Sci USA. 2004;101:13489–13494.
   PubMed Web of Science ®Google Scholar
• Carriere A, Romeo Y, Acosta-Jaquez HA, et al. ERK1/2 phosphorylate Raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J Biol Chem. 2011;286:567–577.
   PubMed Web of Science ®Google Scholar
• Ebi H, Costa C, Faber AC, et al. PI3K regulates MEK/ERK signaling in breast cancer via the Rac-GEF, P-Rex1. Proc Natl Acad Sci USA. 2013;110:21124–21129.
   PubMed Web of Science ®Google Scholar
• Steinbrunn T, Stuhmer T, Gattenlohner S, et al. Mutated RAS and constitutively activated Akt delineate distinct oncogenic pathways, which independently contribute to multiple myeloma cell survival. Blood. 2011;117:1998–2004.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Kimlinger T, Haug J, et al. Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway. PLoS One. 2012;7:e50005.
   PubMed Web of Science ®Google Scholar
• Mimura N, Hideshima T, Shimomura T, et al. Selective and potent Akt inhibition triggers anti-myeloma activities and enhances fatal endoplasmic reticulum stress induced by proteasome inhibition. Cancer Res. 2014;74:4458–4469.
   PubMed Web of Science ®Google Scholar
• Chandarlapaty S, Sawai A, Scaltriti M, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell. 2011;19:58–71.
   PubMed Web of Science ®Google Scholar
• Britschgi A, Andraos R, Brinkhaus H, et al. JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for cotargeting these pathways in metastatic breast cancer. Cancer Cell. 2012;22:796–811.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Kimlinger T, Haug J, et al. TG101209, a novel JAK2 inhibitor, has significant in vitro activity in multiple myeloma and displays preferential cytotoxicity for CD45+ myeloma cells. Am J Hematol. 2010;85:675–686.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Ansell S, Haug J, et al. MRK003, a gamma-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin’s lymphoma. Leukemia. 2012;26:340–348.
   PubMed Web of Science ®Google Scholar
• Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res. 2002;62:5027–5034.
   PubMed Web of Science ®Google Scholar
• Shi Y, Yan H, Frost P, et al. 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. 2005;4:1533–1540.
   PubMed Web of Science ®Google Scholar
• Raje N, Kumar S, Hideshima T, et al. Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood. 2004; 104:4188–4193.
   PubMed Web of Science ®Google Scholar
• 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. 2006;66:2305–2313.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Kimlinger T, Timm M, et al. Multiple mechanisms contribute to the synergistic anti-myeloma activity of the pan-histone deacetylase inhibitor LBH589 and the rapalog RAD001. Leuk Res. 2014;38:1358–1366.
   PubMed Web of Science ®Google Scholar
• Simmons JK, Patel J, Michalowski A, et al. TORC1 and class I HDAC inhibitors synergize to suppress mature B cell neoplasms. Mol Oncol. 2014;8:261–272.
   PubMed Web of Science ®Google Scholar
• Ramakrishnan V, Timm M, Haug JL, et al. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene. 2010;29:1190–1202.
   PubMed Web of Science ®Google Scholar
• Francis LK, Alsayed Y, Leleu X, et al. Combination mammalian target of rapamycin inhibitor rapamycin and HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin has synergistic activity in multiple myeloma. Clin Cancer Res. 2006;12:6826–6835.
   PubMed Web of Science ®Google Scholar
• Baumann P, Hagemeier H, Mandl-Weber S, et al. Myeloma cell growth inhibition is augmented by synchronous inhibition of the insulin-like growth factor-1 receptor by NVP-AEW541 and inhibition of mammalian target of rapamycin by Rad001. Anticancer Drugs. 2009;20:259–266.
   PubMed Web of Science ®Google Scholar
• McMillin DW, Ooi M, Delmore J, et al. Antimyeloma activity of the orally bioavailable dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Cancer Res. 2009;69:5835–5842.
   PubMed Web of Science ®Google Scholar
• Baumann P, Mandl-Weber S, Oduncu F, et al. The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma. Exp Cell Res. 2009;315:485–497.
   PubMed Web of Science ®Google Scholar
• Martin SK, Fitter S, Bong LF, et al. NVP-BEZ235, a dual pan class I PI3 kinase and mTOR inhibitor, promotes osteogenic differentiation in human mesenchymal stromal cells. J Bone Miner Res. 2010;25:2126–2137.
   PubMed Web of Science ®Google Scholar
• Hoang B, Frost P, Shi Y, et al. Targeting TORC2 in multiple myeloma with a new mTOR kinase inhibitor. Blood. 2010;116:4560–4568.
   PubMed Web of Science ®Google Scholar
• Maiso P, Liu Y, Morgan B, et al. Defining the role of TORC1/2 in multiple myeloma. Blood. 2011;118:6860–6870.
   PubMed Web of Science ®Google Scholar
• Cirstea D, Santo L, Hideshima T, et al. Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple myeloma. Mol Cancer Ther. 2014;13:2489–2500.
   PubMed Web of Science ®Google Scholar
• 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. Blood. 2006;107:4053–4062.
   PubMed Web of Science ®Google Scholar
• Aronson LI, Davenport EL, Mirabella F, et al. Understanding the interplay between the proteasome pathway and autophagy in response to dual PI3K/mTOR inhibition in myeloma cells is essential for their effective clinical application. Leukemia. 2013;27:2397–2403.
   PubMed Web of Science ®Google Scholar
• Palacios C, Martin-Perez R, Lopez-Perez AI, et al. Autophagy inhibition sensitizes multiple myeloma cells to 17-dimethylaminoethylamino-17-demethoxygeldanamycin-induced apoptosis. Leuk Res. 2010;34:1533–1538.
   PubMed Web of Science ®Google Scholar
• Villar VH, Nguyen TL, Teres S, et al. Escaping mTOR inhibition for cancer therapy: Tumor suppressor functions of mTOR. Mol Cell Oncol. 2017;4:e1297284.
   PubMed Web of Science ®Google Scholar
• Farag SS, Zhang S, Jansak BS, et al. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res. 2009;33:1475–1480.
   PubMed Web of Science ®Google Scholar
• Guenther A, Baumann P, Burger R, et al. Phase I/II study with single agent everolimus (RAD001) in patients with relapsed or refractory multiple myeloma. Blood. 2009;114:3850–3850.
   Google Scholar
• Gunther A, Baumann P, Burger R, et al. Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study. Haematologica. 2015;100:541–547.
   PubMed Web of Science ®Google Scholar
• Yee AJ, Hari P, Marcheselli R, et al. Outcomes in patients with relapsed or refractory multiple myeloma in a phase I study of everolimus in combination with lenalidomide. Br J Haematol. 2014;166:401–409.
   PubMed Web of Science ®Google Scholar
• Ghobrial IM, Weller E, Vij R, et al. Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study. Lancet Oncol. 2011;12:263–272.
   PubMed Web of Science ®Google Scholar
• Ghobrial IM, Siegel DS, Vij R, et al. TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenstrom’s macroglobulinemia. Am J Hematol. 2016;91:400–405.
   PubMed Web of Science ®Google Scholar
• Richardson PG, Wolf J, Jakubowiak A, et al. Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial. JCO. 2011;29:4243–4249.
   PubMed Web of Science ®Google Scholar
• Jakubowiak AJ, Richardson PG, Zimmerman T, et al. Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study. Br J Haematol. 2012;158:472–480.
   PubMed Web of Science ®Google Scholar
• Spencer A, Yoon SS, Harrison SJ, et al. The novel AKT inhibitor afuresertib shows favorable safety, pharmacokinetics, and clinical activity in multiple myeloma. Blood. 2014;124:2190–2195.
   PubMed Web of Science ®Google Scholar
• Tolcher AW, Patnaik A, Papadopoulos KP, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharmacol. 2015;75:183–189.
   PubMed Web of Science ®Google Scholar