The Role of Proteasome Inhibitors in Treating Acute Lymphoblastic Leukaemia

Abstract

Acute lymphoblastic leukaemia (ALL) is an aggressive haematolymphoid malignancy. The prognosis of ALL is excellent in paediatric population, however the outcome of relapse/refractory disease is dismal. Adult ALL has less favourable prognosis and relapse/refractory disease is not uncommonly encountered. Bortezomib is the first generation proteasome inhibitor licensed to treat plasma cell myeloma and mantle cell lymphoma with favourable side effect profile. Efficacy of bortezomib had been proven in other solid tumors. Clinical studies showed promising response for proteasome inhibitors in treating relapse/refractory ALL. Thus, proteasome inhibitors are attractive alternative agents for research in treating ALL. In the review article, we will introduce different proteasome inhibitors and their difference in pharmacological properties. Moreover, the mechanism of action of proteasome inhibitors on ALL will be highlighted. Finally, results of various clinical studies on proteasome inhibitors in both paediatric and adult ALL will be discussed. This review article provides the insights on the use of proteasome inhibitors in treating ALL with a summary of mechanism of action in ALL which facilitates future research on its use to improve the outcome of ALL.

Interplay between proteasome inhibitors and NF-κB pathway in leukemia and lymphoma: a comprehensive review on challenges ahead of proteasome inhibitors

“…Chymotrypsin-like activity ß5 and β1-subunit in immunoproteasomes as caspase-like activity at lower affinity [ 90 , 91 ].…”

“…β5 site, at higher concentrations, also seems to inhibit the proteolytic β1 and β2 subunits: [ 90 , 98 ]…”

Yeast Ribonucleotide Reductase Is a Direct Target of the Proteasome and Provides Hyper Resistance to the Carcinogen 4-NQO

“…Proteasome inhibitors are used to treat several malignancies, such as multiple myeloma [ 62 , 63 ], mantle cell lymphoma [ 64 ], acute lymphoblastic leukemia [ 65 ], and osteosarcoma [ 66 ]. In combinatorial regimens, proteasome inhibitors can be used together with DNA-damaging therapeutic agents [ 67 , 68 ].…”

From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia

“…Patients with B-ALL have several options available after relapse thanks to the development of the CD19 × CD3 bispecific T-cell engager blinatumomab 37 , the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin 38 , or the chimeric antigen receptor (CAR)-T-cell therapy 39 . Other options, such as the proteasome inhibitor bortezomib 40 and the BCL2 inhibitor venetoclax 41 , have also been reported; nevertheless, their use is currently very limited. In contrast, T-ALL patients upon relapse have limited therapeutic options, restricted to salvage chemotherapy regimens or the chemotherapy agent nelarabine, which is specifically approved for T-ALL after relapse.…”