Editors' ChoiceMultiple Myeloma

Stressing Out the Endoplasmic Reticulum

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Science Translational Medicine  09 May 2012:
Vol. 4, Issue 133, pp. 133ec82
DOI: 10.1126/scitranslmed.3004256

Multiple myeloma (MM), an incurable cancer of antibody-producing white blood cells, is characterized by excessive antibody production—a feature that might lead to its undoing. The high rate of protein synthesis in MM cells stresses the endoplasmic reticulum (ER), where such secreted proteins are produced. To compensate, the cell engages the unfolded protein response (UPR); for example, inositol-requiring enzyme 1α (IRE1α) is activated to splice X-box binding protein 1 (XBP1) mRNA, generating the transcription factor XBP1s. XBP1s then regulates the expression of genes that promote protein folding and degradation in the ER. When the UPR cannot resolve ER stress, however, programmed cell death ensues. Mimura and colleagues examined the importance of this pathway for the survival of MM cells, as well as the ability of a small-molecule inhibitor of IRE1α (MKC-3946) to hamper their growth.

The researchers found that down-regulating XBP1 gene expression with RNA interference or blocking the activity of IRE1α with MKC-3946 substantially inhibited the growth of MM cells and sensitized them to ER stressors such as bortezomib—a drug approved for treating MM—or 17-AAG. The increased stress in the ER induced by inhibition of the IRE1α-XBP1 pathway led to MM cell death despite activation of another branch of the UPR, which inhibits new protein synthesis to decrease the burden on the ER. In contrast, no toxicity was observed in normal white blood cells treated with MKC-3946. MKC-3946 also overcame the protective effects conferred by cytokines such as interleukin-6, which are secreted from bone marrow stromal cells and promote MM cell survival. Furthermore, in a mouse model of MM, treatment with a combination of MKC-3946 and bortezomib not only substantially inhibited tumor growth but also prolonged survival as compared with that in untreated or single agent–treated mice.

This study introduces a new therapeutic strategy for the treatment of MM that involves inhibiting a key survival pathway in the pathogenesis of the disease. These results provide the preclinical rationale for further testing in humans.

N. Mimura et al., Blockade of XBP1 splicing by inhibition of IRE1α is a promising therapeutic option in multiple myeloma. Blood 26 April 2012 (10.1182/blood-2011-07-366633). [Abstract]

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