Author response: Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits
Year: 2015
Type: peer-review
Abstract: Cells have several mechanisms for removing proteins that have been damaged or are no longer needed. One of these mechanisms is carried out by a large protein complex called the proteasome. Drugs that block the proteasome are toxic to all cells, and a type of blood cancer called multiple myeloma is particularly sensitive to these ‘proteasome inhibitors’. However, tumors in patients with multiple myeloma can also become resistant to these drugs. Using a genetic approach, Acosta-Alvear et al. identified the factors that control the sensitivity of cells to proteasome inhibitors. In particular, reducing the levels of other factors that contribute to protein balance made the cells more sensitive. Using a combination of proteasome inhibitors and drugs that target these other factors could prove to be useful in the fight against multiple myeloma. The proteasome complex contains two types of subunits: regulatory subunits that recognize the proteins that need to be degraded, and catalytic subunits that degrade the proteins. The results of Acosta-Alvear et al. revealed how varying the levels of these two subunits influenced the sensitivity of cells to inhibitors. While decreasing the levels of catalytic subunits made the cells more sensitive, as expected, decreasing the level of regulatory subunits surprisingly made the cells resistant to the inhibitors. A possible explanation for this paradoxical result is that certain proteins are less effectively degraded by the proteasome in these cells, and that the buildup of these proteins protects the cells against the drugs. Acosta-Alvear et al. also found that lower levels of regulatory subunits desensitized multiple myeloma patients to therapy based on proteasome inhibition, suggesting that results from the genetic screen carried out in cells can predict clinical resistance mechanisms and guide the development of future therapies to increase patient survival.
Source: eLife
Institutions: Howard Hughes Medical Institute, University of California, San Francisco, University of Copenhagen, Novo Nordisk Foundation, National Institutes of Health, National Institutes of Health Clinical Center, Memorial Sloan Kettering Cancer Center, National Cancer Institute, National Cancer Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W2987396771