Inhibition of mTORC1 activity by REDD1 induction in myeloma cells resistant to bortezomib cytotoxicity

The combination of bortezomib and dexamethasone is becoming the reference induction treatment for multiple myeloma patients younger than 65 years. Despite its advantage over vincristin adryamicin dexamethasone induction treatment, bortezomib does not benefit all patients. We hypothesize that heterogeneity of the response experienced by myeloma patients is, at least in part, due to genomic variations in the malignant plasma cells. To test this hypothesis we used gene expression profiling to identify early responsive genes induced by bortezomib in resistant myeloma cells. Our study revealed: (i) a dramatic induction of REDD1, a negative regulator of mammalian target of rapamycin kinase complex 1 (mTORC1) activity, in these cells; (ii) a transient cell size decrease associated with REDD1 overexpression; and (iii) partial restoration of bortezomib sensitivity in REDD1 knockdown bortezomib-resistant myeloma cells. Together, these results identify a possible novel mechanism of bortezomib resistance in myeloma patients mediated by REDD1 overexpression involving inhibition of mTORC1 activity and suggest that the use of mammalian target of rapamycin inhibitors in myeloma patients could be deleterious. (Cancer Sci 2010; 101: 889–897)