Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple Myeloma

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

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Despite promising preclinical results with mTOR kinase inhibitors in multiple myeloma, resistance to these drugs may arise via feedback activation loops. This concern is especially true for insulin-like growth factor1 receptor (IGF1R), because IGF1R signaling is downregulated by multiple AKT and mTOR feedback mechanisms. We have tested this hypothesis in multiple myeloma using the novel selective mTOR kinase inhibitor AZD8055.Weevaluated p-mTOR S2481 as the readout for mTORC2/Akt activity in multiple myeloma cells in the context of mTOR inhibition via AZD8055 or rapamycin. We next validated AZD8055 inhibition of mTORC1 and mTORC2 functions in multiple myeloma cells alone or in culture with bone marrow stroma cells and growth factors. Unlike rapamycin, AZD8055 resulted in apoptosis of multiple myeloma cells. AZD8055 treatment, however, induced upregulation of IGF1R phosphorylation in p-Akt S473-expressing multiple myeloma cell lines. Furthermore, exposure of AZD8055-treated cells to IGF1 induced p-Akt S 473 and rescued multiple myeloma cells from apoptosis despite mTOR kinase inhibition and TORC2/Akt blockage. The addition of blocking IGF1R antibody resulted in reversing this effect and increased AZD8055-induced apoptosis. Our study suggests that combination treatment with AZD8055 and IGF1R-blocking agents is a promising strategy in multiple myeloma with potential IGF1R/Akt signaling-mediated survival. Mol Cancer Ther; 13(11); 2489-500.

Original languageEnglish (US)
Pages (from-to)2489-2500
Number of pages12
JournalMolecular Cancer Therapeutics
Volume13
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Fingerprint

Multiple Myeloma
Phosphotransferases
Insulin
Growth
Sirolimus
Apoptosis
(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
mechanistic target of rapamycin complex 1
Insulin Receptor
Drug Resistance
Bone Marrow Cells
Intercellular Signaling Peptides and Proteins
Up-Regulation
Down-Regulation
Phosphorylation
Cell Line
Antibodies
TOR complex 2
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cirstea, D., Santo, L., Hideshima, T., Eda, H., Mishima, Y., Nemani, N., ... Raje, N. (2014). Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple Myeloma. Molecular Cancer Therapeutics, 13(11), 2489-2500. https://doi.org/10.1158/1535-7163.MCT-14-0147

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; Gorgun, Gullu; Hu, Yiguo; Ohguchi, Hiroto; Suzuki, Rikio; Cottini, Francesca; Guichard, Sylvie M.; Anderson, Kenneth C.; Raje, Noopur.

In: Molecular Cancer Therapeutics, Vol. 13, No. 11, 01.11.2014, p. 2489-2500.

Research output: Contribution to journalArticle

Cirstea, D, Santo, L, Hideshima, T, Eda, H, Mishima, Y, Nemani, N, Mahindra, A, Yee, A, Gorgun, G, Hu, Y, Ohguchi, H, Suzuki, R, Cottini, F, Guichard, SM, Anderson, KC & Raje, N 2014, 'Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple Myeloma', Molecular Cancer Therapeutics, vol. 13, no. 11, pp. 2489-2500. https://doi.org/10.1158/1535-7163.MCT-14-0147
Cirstea, Diana ; Santo, Loredana ; Hideshima, Teru ; Eda, Homare ; Mishima, Yuko ; Nemani, Neeharika ; Mahindra, Anuj ; Yee, Andrew ; Gorgun, Gullu ; Hu, Yiguo ; Ohguchi, Hiroto ; Suzuki, Rikio ; Cottini, Francesca ; Guichard, Sylvie M. ; Anderson, Kenneth C. ; Raje, Noopur. / Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple Myeloma. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 11. pp. 2489-2500.
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AU - Mishima, Yuko

AU - Nemani, Neeharika

AU - Mahindra, Anuj

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AU - Gorgun, Gullu

AU - Hu, Yiguo

AU - Ohguchi, Hiroto

AU - Suzuki, Rikio

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