Review Updates Mechanisms Underlying Proteasome Inhibitor Resistance in MM

Drug resistance continues to be a major problem in proteasome inhibitor (PI) therapy for patients with multiple myeloma (MM).

In a new review article, investigators outlined some of the latest findings related to the mechanisms of PI resistance, and stressed the importance of overcoming the problem.

Writing in the Asia-Pacific Journal of Clinical Oncology, coauthors Yang Bai, PhD, and Xing Su, PhD, explained that since the approval of the first PI, bortezomib (Velcade) in 2003, outcomes for patients with MM have improved significantly.

“Interestingly, it has been reported that the 5-year relative survival rate of MM increased by 49% from 2005 to 2011,” Bai and Su reported. Both authors are affiliated with the First Hospital of Jilin University, in China.

PIs target the 26S proteasome. Bortezomib works primarily by inhibiting the chymotrypsin-like site of the 20S proteolytic core, explained Su and Bai, which in turn induces cell-cycle arrest and apoptosis by suppressing NF‐κB signaling. MM cells express a higher level of NF‐κB activation signature molecules, compared to normal hematopoietic cells, they said.

“IκB, the inhibitory factor of NF‐κB, is the substrate of 26S proteasome,” they wrote. “PI causes the accumulation of IκB which results in blocking nuclear translocation of NF‐κB and displayed antitumor activity against MM cells.”

The authors said several mechanisms are suspected to be involved in drug resistance. Specific target mutations and genetic changes in the target gene or other signaling genes of signal transduction have been implicated in primary resistance, they said.

“Though culturing TH1 cells in escalating concentrations of bortezomib, the first reported point mutation in PI resistance is a single point mutation to the binding pocket of the β5 subunit (PSMB5) which mapped to the cluster region in the catalytic site (Ala49Val),” they said. “The mutation was found to interfere with the spatial construction of the bortezomib binding pocket, resulting in drug resistance.”

Other mutations, such as in the binding pocket of the β5 subunit, have been identified in MM patients.

Other mechanisms believed to play a role in resistance include key stress signaling pathways, apoptosis failure and autophagy activation, and aberrant expression of proteasomal subunits, among other processes.

Bai and Su said there is an “urgent need” to overcome PI resistance. They said a number of drugs have been developed that could the problem, either as single-agent therapies or in combination with other agents..

Among them are venetoclax (Venclexta), a BCL-2 inhibitor.

“Combined autophagy inhibitors bafilomycin A [and] chloroquine with the p62 inhibitor verteporfin increased cytotoxicity and synergistic activity with bortezomib,” they said. “Selinexor, a reversible inhibitor of XPO1, overcomes acquired PI resistance associated with bortezomib or carfilzomib in MM patients.”

New research also suggests miR-126b is a negative regulator of p53, which could be a meaningful agent because overexpression of miR-125b leads to suppression of the endogenous level of p53.

Bai and Su concluded that drug resistance is currently inevitable after long-term treatment with PIs.

“It is necessary to unravel the mechanism of drug resistance in MM in order to improve novel therapeutic strategies for refractory and relapsed patients,” they said. “In addition, more extensive basic research and clinical trials are required for combination therapy regimens, the development of newer PIs, and reduction of drug toxicity.”

Reference

Bai Y, Su X. Updates to the drug-resistant mechanism of proteasome inhibitors in multiple myeloma. Asia Pac J Clin Oncol. Published online September 13, 2020. doi:10.1111/ajco.13459