Kenneth Anderson, MD
2010-03-01
Dr. Anderson has served as a consultant on the Advisory Board for Millennium: The Takeda Oncology Company.
Yarde DN, Oliveira V, Mathews L, et al. Targeting the Fanconi anemia/BRCA
pathway circumvents drug resistance in multiple myeloma.
Cancer Res. 2009;69:9367-75.
In this paper, Yarde and colleagues from H. Lee Moffitt
Cancer Center provide for the first time evidence that NF-κB
subunits RelB/p50 transcriptionally activate the Fanconi
anemia/BRCA (FA/BRCA) pathway in myeloma. Their previous
studies have implicated activation of this pathway mediating
melphalan resistance in myeloma; importantly, in this study,
they demonstrated that NF-κB inhibition by siRNA, IkB kinase
blockade, or the proteasome inhibitor bortezomib decreased
FA/BRCA gene expression in myeloma, thereby decreasing
DNA damage repair and enhancing tumor cell sensitivity to
melphalan. These studies therefore suggest that targeting FA/BRCA may enhance sensitivity or overcome drug resistance in
myeloma.
The majority of multiple myeloma cells are initially sensitive to
DNA damaging agents, including alkylating agents and anthracyclines,
but inevitably acquire resistance correlating with the
level of clinical exposure. Moreover, this drug-resistant phenotype
is associated with progression of disease. Importantly, in
preclinical studies and clinical trials, the proteasome inhibitor
bortezomib can overcome resistance to conventional agents,
including DNA-damaging agents. A randomized trial in relapsed
refractory myeloma showed increased rate and extent
of response, as well as prolonged progression-free and overall
survival, in a patient cohort treated with pegylated liposomal
doxorubicin and bortezomib versus bortezomib alone. Most
recently, another landmark randomized trial in newly diagnosed
elderly patients with myeloma further confirmed that adding
bortezomib to DNA-damaging agent melphalan with prednisone
(MP) markedly increased both response and survival compared
to MP alone. The mechanism whereby bortezomib sensitizes or
overcomes resistance to alkylating agents, however, was not
previously defined.
The original premise for the use of bortezomib in myeloma was
inhibition of NF-κB activation, which is implicated in tumor cell
survival and drug resistance, modulation of myeloma cell adhesion
to extracellular matrix proteins and bone marrow stromal
cells, and secretion of cytokines in the bone marrow milieu.
Bortezomib clearly has multiple activities other than NF-κB activation
on the one hand, and the biologic phenotype of inhibition
of NF-κB is not fully defined on the other. Moreover, bortezomib
may even activate NF-κB in some myeloma cells, depending
on whether canonical or non-canonical activation mechanisms
are present. Prior studies from Dalton and colleagues have
implicated the FA/BRCA pathway in conferring melphalan
resistance, and the current elegant study provides convincing
evidence that constitutive activation of NF-κB in myeloma
results in activation of this pathway both in myeloma cell lines
and patient cells. Most importantly, either selective knockdown
of NF-κB p50/RelB or bortezomib can sensitize or overcome
melphalan resistance. This study not only delineates another
mechanism of melphalan resistance and strategy for overcoming
it with proteasome inhibitors preclinically, but it also has other
important implications. Since melphalan remains a mainstay
of treatment for newly diagnosed myeloma, at low doses with
prednisone in older patients and at high doses in candidates
for stem cell transplantation, this study lends further support for
incorporation of bortezomib in front-line therapy. It also suggests
the therapeutic potential of developing therapies selectively
targeting the FA/BRCA pathway to overcome drug resistance,
thereby improving patient outcome.
Although the promise of this combination therapy is great, we
need to carefully monitor for long-term sequelae when combining
DNA-damaging agents with proteasome inhibitors in
patients who are living longer as a result of novel therapies.
Nonetheless, this study is a wonderful example of delineating
the function of a novel pathway in myeloma, with bench-to-bedside
translation and important clinical applications for the future.
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