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Ref Type Journal Article
PMID (22538852)
Authors Mimura N, Fulciniti M, Gorgun G, Tai YT, Cirstea D, Santo L, Hu Y, Fabre C, Minami J, Ohguchi H, Kiziltepe T, Ikeda H, Kawano Y, French M, Blumenthal M, Tam V, Kertesz NL, Malyankar UM, Hokenson M, Pham T, Zeng Q, Patterson JB, Richardson PG, Munshi NC, Anderson KC
Title Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma.
Journal Vol Issue Date Pages Journal Short Title
Blood 119 24 2012 Jun 14 5772-81 Blood
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MKC-3946 MKC-3946 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MKC-3946 MKC 3946|MKC3946 MKC-3946 is small molecule drug that targets the endoribonuclease domain of Ire1 alpha (ERN1) and inhibits XBP1 splicing, potentially resulting in increased apoptosis and decreased tumor growth (PMID: 22538852).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References