title: Delineating the mTOR kinase pathway using a dual TORC1/2 inhibitor, AZD8055, in multiple myeloma.
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 factor 1 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. We evaluated p-mTOR S(2481) 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 S(473)-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.
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Diana
authors.initials: D
authors.lastname: Cirstea
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Homare
authors.initials: H
authors.lastname: Eda
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Nemani
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Anuj
authors.initials: A
authors.lastname: Mahindra
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew
authors.initials: A
authors.lastname: Yee
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Gullu
authors.initials: G
authors.lastname: Gorgun
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Hu
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottini
authors.affiliation: AstraZeneca, Alderley Park, Macclesfield, United Kingdom.
authors.forename: Sylvie M
authors.initials: SM
authors.lastname: Guichard
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts. nraje@partners.org.
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009025:Morpholines / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D009025:Morpholines; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases