Fellowship: Lin Ao: Novel resistance mechanisms to proteasome inhibitor chemotherapy

The proteasome is a large protein complex responsible for the degradation of >80% of cellular proteins. It is the major player of the highly-regulated ubiquitin-proteasome system, which is important in controlling a myriad of cellular processes. It has been previously demonstrated that fast-dividing cancer cells are more reliant on proteasome activity for growth and survival. Based on this, the proteasome was exploited as a potential anti-cancer target. This lead to the development of proteasome inhibitor agents bortezomib and carfilzomib that now comprise a class of chemotherapy that is integral to the treatment of multiple myeloma. However, one of the major challenges in the continued use of proteasome inhibitor therapy is drug resistance. Thus, in order to expand the therapeutic utility of proteasome inhibitor agents, it is important to understand the mechanisms underlying the inherent differences in sensitivity as well as the development of acquired resistance. Several mechanisms of PI resistance have been proposed previously, however these mechanisms have not been identified in the clinic, nor do they account for all proteasome inhibitor resistance observed. In this regard, our goal is to identify additional mechanisms that may be responsible for the development of proteasome inhibitor resistance. In the current proposal, we hypothesize that accelerated proteasome turnover via autophagy-mediated processes may contribute to the development of proteasome inhibitor resistance in cancer cells. This is based on our preliminary findings indicating that carfilzomib-resistant cells have rapid recovery of proteasome activity following initial inhibition at a rate that is faster than the expected proteasome turnover rate. We will validate our hypothesis by comparing the rates of proteasome turnover in pancreatic cancer cell line models with different sensitivities to proteasome inhibition. We will also investigate the involvement of the autophagy-lysosome pathway in the degradation of proteasomes, as well as the role of autophagy in the development of proteasome inhibitor resistance. These studies may provide additional insight into the molecular changes responsible for the development of resistance. Such information may be important for the design of next-generation proteasome inhibitors, or alternative combination therapies to overcome resistance.