Fellowship: Kimberly Carmony: Role of Proteasome Catalytic Subunit Composition in Proteasome Inhibitor Resistance

Proteasomes are multiprotease complexes which execute the tightly controlled degradation of proteins, thereby regulating many important cellular processes. The FDA approval of two proteasome inhibitors—bortezomib and carfilzomib—has validated the proteasome as a chemotherapeutic target. Although these inhibitors have markedly improved clinical outcomes, many patients are intrinsically resistant to their anticancer effects, and those who do initially respond will acquire resistance over time. However, the underlying mechanisms of intrinsic and acquired resistance to proteasome inhibitor drugs remain unclear. Bortezomib and carfilzomib target two distinct proteasome subtypes—the constitutive proteasome and immunoproteasome—which differ in their unique sets of catalytic subunits. In addition to these two well-recognized subtypes, ‘intermediate’ proteasome subtypes containing a non-standard mixture of constitutive proteasome and immunoproteasome catalytic subunits have been identified. Previous studies have indicated that the expression levels of specific proteasome catalytic subunits correlate with the degree of intrinsic sensitivity of cancer cells to proteasome inhibitors. Additionally, studies conducted in our laboratory and others have demonstrated that prolonged exposure of cancer cells to proteasome inhibitors leads to nonconcerted changes in the expression levels of proteasome catalytic subunits, possibly resulting in the formation of intermediate proteasomes. Based on these results, we hypothesize that proteasome catalytic subunit composition contributes to intrinsic and acquired resistance of cancer cells to proteasome inhibitors. We propose the following specific aims to test this hypothesis: 1) Determine whether distinct proteasome subtypes contribute to intrinsic resistance of cancer cells to proteasome inhibitors, and 2) Determine whether changes in proteasome subtypes contribute to acquired resistance of cancer cells to proteasome inhibitors. Results from this study may reveal a novel mechanism of proteasome inhibitor resistance. Additionally, they may provide valuable information for designing novel inhibitors that can overcome this resistance by more effectively targeting specific intermediate proteasome subtypes.