66IN - Proteasome Inhibitors: Really a Targeted Therapy?

Abstract

ABSTRACT Bortezomib is the first-in-class proteasome inhibitor that targets the critical process of intracellular protein modification and degradation. In 2006, bortezomib was approved for the treatment of relapsed or refractory MCL. The mechanisms of proteasome inhibition are very complex as they affect many pathways. The Initial rationale for bortezomib use was inhibition of NF-kB activity. However, bortezomib does not block constitutive NF-kB activity in MCL and induces oxidative and endoplasmic reticulum (ER) stress. This cellular stress leads to the activation of a cytoprotective response called Unfolded Protein Response (UPR), that tries to aliviate ER stress and rescue the cell by different adaptive mechanisms. However under conditions of prolonged stress, apoptosis is activated. Apoptosis commitment starts with the transcriptional activation of the propapoptotic BH3-only protein Noxa, leading to mitochondrial apoptosis. However, half of MCL cases fail to respond, and resistance often appears after initial treatment. By gene expression analysis it has been reported that MCL bortezomib-resistant cell lines showed partial plasmacytic differentiation, including increased expression of IRF4 and its target genes, and of the cell-surface markers CD38 and CD138. Tumors from patients with inferior clinical responses to bortezomib also had high IRF4 and CD38 expression, identifying possible clinical markers of bortezomib resistance. Also, a correlation between loss of sensitivity to bortezomib and up-regulation of the prosurvival chaperone BiP/Grp78 controlling ER homeostasis has been observed. BiP/Grp78 forms a large multiprotein complex with other ER molecular chaperones, including HSP90. Combination of bortezomib with IPI-504, a HSP90 inhibitor that displace the client proteins and target them for destruction by the proteasome system, prevented BiP/Grp78 accumulation, thereby promoting apoptosis and inhibiting the growth of bortezomib-resistant tumor xenotransplants. In summary, targeting the ubiquitin-proteasome pathway with bortezomib represents a potent arsenal in the treatment of MCL, although we need to find new combinations and specific biomarkers that may help us to recognize which cases will be benefit from each specific treatment. Disclosure All authors have declared no conflicts of interest.