title: Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma.
abstract: Multiple myeloma (MM) cells are characterized by high protein synthesis resulting in chronic endoplasmic reticulum (ER) stress, which is adaptively managed by the unfolded protein response. Inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, thereby increasing XBP1s protein, which in turn regulates genes responsible for protein folding and degradation during the unfolded protein response. In this study, we examined whether IRE1α-XBP1 pathway is a potential therapeutic target in MM using a small-molecule IRE1α endoribonuclease domain inhibitor MKC-3946. MKC-3946 triggered modest growth inhibition in MM cell lines, without toxicity in normal mononuclear cells. Importantly, it significantly enhanced cytotoxicity induced by bortezomib or 17-AAG, even in the presence of bone marrow stromal cells or exogenous IL-6. Both bortezomib and 17-AAG induced ER stress, evidenced by induction of XBP1s, which was blocked by MKC-3946. Apoptosis induced by these agents was enhanced by MKC-3946, associated with increased CHOP. Finally, MKC-3946 inhibited XBP1 splicing in a model of ER stress in vivo, associated with significant growth inhibition of MM cells. Taken together, our results demonstrate that blockade of XBP1 splicing by inhibition of IRE1α endoribonuclease domain is a potential therapeutic option in MM.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Mimura
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Fulciniti
authors.forename: Gullu
authors.initials: G
authors.lastname: Gorgun
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Diana
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authors.lastname: Cirstea
authors.forename: Loredana
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authors.lastname: Santo
authors.forename: Yiguo
authors.initials: Y
authors.lastname: Hu
authors.forename: Claire
authors.initials: C
authors.lastname: Fabre
authors.forename: Jiro
authors.initials: J
authors.lastname: Minami
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.forename: Tanyel
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authors.lastname: Kiziltepe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawano
authors.forename: Maureen
authors.initials: M
authors.lastname: French
authors.forename: Martina
authors.initials: M
authors.lastname: Blumenthal
authors.forename: Victor
authors.initials: V
authors.lastname: Tam
authors.forename: Nathalie L
authors.initials: NL
authors.lastname: Kertesz
authors.forename: Uriel M
authors.initials: UM
authors.lastname: Malyankar
authors.forename: Mark
authors.initials: M
authors.lastname: Hokenson
authors.forename: Tuan
authors.initials: T
authors.lastname: Pham
authors.forename: Qingping
authors.initials: Q
authors.lastname: Zeng
authors.forename: John B
authors.initials: JB
authors.lastname: Patterson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D016227:Benzoquinones / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D012326:RNA Splicing / Q000187:drug effects* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D001897:Boronic Acids; D000069286:Bortezomib; D004268:DNA-Binding Proteins; D004722:Endoribonucleases; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D047029:Lactams, Macrocyclic; D017346:Protein Serine-Threonine Kinases; D011719:Pyrazines; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C112765:tanespimycin; C528229:ERN1 protein, human