Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma

Cirstea, Diana; Santo, Loredana; Hideshima, Teru; Eda, Homare; Mishima, Yuko; Nemani, Neeharika; Mahindra, Anuj; Yee, Andrew J.; Görgün, Güllü; Hu, Yiguo; Ohguchi, Hiroto; Suzuki, Rikio; Cottini, Francesca; Guichard, Sylvie; Anderson, Kenneth C.; Raje, Noopur

doi:10.1158/1535-7163.mct-14-0147

Cited by 24 publications

(18 citation statements)

References 24 publications

(40 reference statements)

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“…While these drugs inhibit only mTORC1 and lead to activation of Akt due to negative feedback of mTORC2 [77], dual inhibition of mTORC1 and mTORC2 in MM cells demonstrates significant growth inhibition [78]. Moreover, dual inhibition of PI3K/mTOR or insulin-like growth factor 1 receptor (IGF1R)/mTOR also triggers significant anti-tumor effects in MM [79, 80]. …”

Section: Targeting Signal Transductionmentioning

confidence: 99%

Novel therapeutic strategies for multiple myeloma

Mimura

Hideshima

Anderson

2015

Experimental Hematology

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Multiple Myeloma (MM) is a plasma cell malignancy which remains incurable despite of the recent emergence of multiple novel agents. Importantly, recent genetic and molecular analyses have revealed the complexity and heterogeneity of this disease, highlighting the need for therapeutic strategies to eliminate all the clones. Moreover, the bone marrow microenvironment, including stromal cells and immune cells, plays a central role in MM pathogenesis, promoting tumor cell growth, survival, and drug resistance. New classes of agents including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors have shown remarkable efficacy; however, novel therapeutic approaches are still urgently needed to further improve patient outcome. In this review, we discuss the recent advances and future strategies to ultimately develop MM therapies with curative potential.

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Section: Targeting Signal Transductionmentioning

confidence: 99%

Novel therapeutic strategies for multiple myeloma

Mimura

Hideshima

Anderson

2015

Experimental Hematology

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“…This is especially so since previous work has demonstrated anti-MM efficacy of dual TORC1/TORC2 inhibitors (28) as well as AKT inhibitors (29). However, several studies (1, 5) clearly demonstrate that the adverse effect of DEPTOR gene silencing in MMCLs is prevented by RAPTOR knockdown, thus implicating TORC1 activation.…”

Section: Discussionmentioning

confidence: 95%

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

et al. 2016

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DEPTOR is a 48kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Over-expression of DEPTOR specifically occurs in a model of multiple myeloma (MM). Its silencing in MM cells is sufficient to induce cytotoxicity, suggesting DEPTOR is a potential therapeutic target. mTORC1 paralysis protects MM cells against DEPTOR silencing, implicating mTORC1 in DEPTOR’s critical role in MM cell viability. Building on this foundation, we interrogated a small molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR-mTOR binding in human myeloma cells with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell cycle arrest in MM cell lines and prevented outgrowth of human MM cells in immunodeficient mice. In vitro cytotoxicity against MM cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary MM cells while normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in MM and suggest an effective strategy of preventing binding of DEPTOR to mTOR.

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“…In vitro and in vivo studies showed that dual mTORC1/C2 inhibitor is more active against myeloma cells than mTORC1 inhibition alone (rapamycin) that could results in the feedback activation of AKT [27, 46]. But one major weakness of mTORC1/C2 inhibitor treatment is that it induces upregulation of IGF-1 receptor phosphorylation in MM cell lines, which rescues myeloma cells from apoptosis despite mTOR kinase inhibition and mTORC2/AKT blockage [47]. Given these observation and the fact that exogenous IGF-1 did not reverse GSK-470-induce cell death and GSK-470 could not inhibit mTORC2, there is a need to combine dual mTORC1/C2 inhibitor with GSK-470 to target and overcome these resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242

et al. 2017

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A deeper understanding of the complex pathogenesis of multiple myeloma (MM) continues to lead to novel therapeutic approaches. Prior studies suggest that 3-phosphoinositide-dependent kinase 1 (PDK1) is expressed and active, acting as a crucial regulator of molecules that are essential for myelomagenesis. In the present study, we show that GSK2334470 (GSK-470), a novel and highly specific inhibitor of PDK1, induces potent cytotoxicity in MM cell lines including Dexamethasone-resistant cell line, but not in human normal cells. Insulin-like growth factor-1 could not rescue GSK-470-induced cell death. Moreover, GSK-470 down-modulates phosphor-PDK1, thereby inhibiting downstream phosphor-AKT at Thr308 and mTOR complex 1 (mTORC1) activity. However, GSK-470 could not affect mTORC2 activity and phosphor-AKT at Ser473. RPMI 8226 and OPM-2 cells with low expression of PTEN show relative resistant to GSK-470. Knockout of PTEN by shRNA resulted in a partial reversion of GSK-470-mediated growth inhibition, whereas overexpression of PTEN enhanced myeloma cell sensitivity to GSK-470, suggesting that the sensitivity to GSK-470 is correlated with PTEN expression statue in MM cells. Combining PP242, a dual mTORC1/C2 inhibitor, with GSK-470, had greater antimyeloma activity than either one alone in vitro and in MM xenograft model established in immunodeficient mice. In particular, this combination was able to result in a complete inhibition of mTORC1/C2 and full activity of AKT. Together, these findings raise the possibility that combining PDK1 antagonist GSK-470 with mTORC1/C2 inhibitors may represent a novel strategy against MM including drug-resistant myeloma, regardless of PTEN expression status.

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Delineating the mTOR Kinase Pathway Using a Dual TORC1/2 Inhibitor, AZD8055, in Multiple Myeloma

Cited by 24 publications

References 24 publications

Novel therapeutic strategies for multiple myeloma

Novel therapeutic strategies for multiple myeloma

Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells

PDK1 inhibitor GSK2334470 exerts antitumor activity in multiple myeloma and forms a novel multitargeted combination with dual mTORC1/C2 inhibitor PP242

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