Cap dependent translation contributes to resistance of myeloma cells to bortezomib

Multiple myeloma is the second most predominant blood malignancy. Proteasome inhibitors like bortezomib have increased life expectancy, but eventually patients develop resistance to therapy. It was proposed that bortezomib acts through the induction of the Unfolded Protein Response (UPR), i.e. an accumulation of misfolded proteins that can cause a lethal stress response. By this theory, increasing the proteasome load by the stimulation of translation may worsen the UPR. We evaluated the crosstalk between translation and bortezomib toxicity in sensitive as well as bortezomib resistant cells. We found that bortezomib toxicity did not correlate with induction of the UPR but caused a late reduction in global translation. The reduction of translation was accompanied by dephosphorylation of the mTORC1 target 4E-BP1. Infection of myeloma cells with mutant forms of 4E-BP, constitutively dephosphorylated, worsened bortezomib induced cell death. Since mTORC1 inhibitors cause pharmacological inhibition of 4E-BP phosphorylation, we tested whether they could act synergistically with bortezomib. We found that rapamycin, a specific mTORC1 blocker, and PP242 a mTOR antagonist induce the arrest of myeloma cells, irrespective of BZ sensitivity. Sensitivity to mTOR inhibitors (rapalogs) has been associated to the levels of eIF4E/4E-BPs. Low eIF4E/4E-BP ratio in malignant cells predicts sensitivity to rapalogs. We found that levels of eIF4E and 4E-BPs are variable among patients, and that 15% of myeloma patients have high levels of 4E-BP1/2 compared to the levels of eIF4E. Primary cells of myeloma retain sensitivity to mTOR inhibition, when plated on stromal cells. We propose that translational load does not contribute to bortezomib-induced death, but rather mTOR targeting may be successful in bortezomib resistant patients, stratified for eIF4E/4EBPs. In conclusion translation load in myeloma cells is not contributing to proteasome-induced cell death. We provide a rationale for treating patients with multiple myeloma with mTOR inhibitors, independently from their response to bortezomib.