By Kenneth Anderson, MD
2009-07-01
Dr. Anderson receives research funding and/or consultancy fees from Millennium, Celgene, and Novartis.
Bianchi G, Oliva L, Cascio P et al. The
proteasome load versus capacity balance determines apoptotic
sensistivity of multiple myeloma cells to proteasome inhibition. Blood. 2009;113:3040-9.
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.
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.
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