The use of proteasome inhibitors to treat cancer has been greatly limited by the ability of cancer cells to develop resistance to these drugs. But researchers have found a mechanism underlying this resistance--a mechanism that naturally occurs in many diverse cancer types and that may expose vulnerabilities to drugs that spur the natural cell-death process.

This finding--which also identifies a biomarker that can be used to gain a deeper understanding of the proteasome inhibitor-resistant state-- is reported in the Proceedings of the National Academy of Sciences (PNAS) in an article entitled, Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers.

Proteasomes are large protein complexes that mediate protein degradation and play a crucial role in maintaining protein equilibrium within the cell. When cells become cancerous, tremendous stresses are placed on the cellular machinery responsible for maintaining protein equilibrium--and that machinery is the target of anti-cancer drugs called proteasome inhibitors. Although proteasome inhibitors are very efficient in selective killing of cancer tumor cells grown in a dish (in-vitro), their success in the clinic has largely been undermined by the development of resistance--mechanisms of which are poorly understood.

Analyzing data from thousands of cancer lines and tumors, the researchers found that those demonstrating resistance to proteasome inhibitor drugs were marked by suppressed expression of one or more of the cells' proteasome cap subunits (which are a subsets of the larger proteasome). Suppressing the expression of even one of the many subunits making up the cap will impair the assembly of the whole cap, resulting in a proteasome-inhibitor resistant state.

Nevertheless, this new report reveals a strategy to address such resistance which may have broad utility. The researchers found that, beyond conferring resistance to proteasome inhibitors, the suppressed expression of proteasome subunits reflects a broad remodeling of the cell's gene signature. Furthermore, this can also serve as a biomarker to stratify patients for treatment.

http://www.pnas.org/content/early/2016/12/23/1619067114.abstract?sid=cd964b2d-ada1-44b1-809e-865c04541e2a