Cenci and colleagues from Milan reported on the relationship between proteasome expression and workload within tumor cells and their response to proteasome inhibitor (PI) therapy. Specifically, they characterized multiple myeloma (MM) cell lines and showed that those with low proteasome expression and higher workloads were more sensitive to PI than those with higher proteasome expression and lower workloads, which are resistant to PI treatment. They varied proteasome expression and workload to confirm a cause-effect relationship of proteasome stress to PI sensitivity. Importantly, in patient MM cells, they demonstrated an inverse relationship between proteasome activity and sensitivity to PI treatment.
Bortezomib PI therapy can overcome cell-adhesion-mediated drug resistance to conventional therapies in both in vitro and in vivo models of MM cells in the bone marrow (BM) microenvironment. Responses to bortezomib, including some CRs, were observed in phase I clinical trials in relapsed refractory MM3, and, most importantly, bortezomib therapy has led to durable responses with associated clinical benefit in patients with relapsed refractory, relapsed, and newly diagnosed MM, providing basis for its FDA and EMEA approval for treatment in these settings in 2003, 2005, and 2008. However, not all patients respond, and those who do eventually develop resistance. In this study, Cenci and coworkers defined a possible mechanism for this differential PI responsiveness, predicated upon proteasome stress within patient MM cells, reflecting the balance between proteasome expression and workload. These exciting studies on MM cells and patient cells require validation in large ongoing studies of PI therapies in MM and other cancers, but they have great promise to allow selection of those patients most likely to respond.
Resistance to PI therapy has been attributed to mutations in proteasome subunits, insufficient extent or breadth of PI subunit inhibition, induction of heat shock protein (hsp) 27 and 90, as well as compensatory induction of aggresomal protein degradation. Ongoing efforts to overcome these mechanisms of resistance have rapidly translated from the bench to the bedside in related clinical trials. For example, hsp 90 inhibitor tanespimycin blocks induction of hsp 90 triggered by bortezomib and was shown to enhance sensitivity or overcome resistance to bortezomib in preclinical and phase I/II clinical trials. Both carfilzomib and CEP-18770 more potently inhibit the chymotryptic-like activity of the proteosome than does bortezomib, whereas NPI0052 inhibits the chymotryptic-like activity as well as the tryptic-like and caspase-like activities; all overcome bortezomib resistance in preclinical studies and are undergoing clinical evaluation. Altun and colleagues recently described a selective b1 immunoproteasome inhibitor, which can overcome preclinical bortezomib resistance, providing the framework for clinical trials of selective immunoproteasome inhibitors in MM.
We have shown in preclinical models that combinations of proteasome inhibitors bortezomib and NPI0052, even at doses that are ineffective alone, can achieve synergistic cytotoxicity with a very favorable side effect profile. Finally, we have shown that bortezomib up-regulates aggresomal degradation of ubiquitinated proteins; addition of histone deacetylases tubacin, vorinostat, or panobinostat can overcome bortezomib resistance, and combination clinical trials are promising.
In Brief
The model proposed here by Cenci and colleagues may be useful, not only to predict tumor cell response to PI therapy, but also to inform the design of such combination studies. Importantly, analysis of proteasome stress in preclinical as well as ongoing and future clinical trials will validate its scientific and prognostic utility, not only in MM, but also in other cancers.
Competing Interests
Dr. Anderson receives research funding and/or consultancy fees from Millennium, Celgene, and Novartis.
