Cell Cycle IBRUTinib: BRUTe Force against

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IBRUTinib: BRUTe Force against Bortezomib-Resistant
Myeloma Cells
a
a
Lingling Xian , Carol Ann Huff & Ms Linda Resar
abc
a
Department of Medicine; The Johns Hopkins University School of Medicine, Baltimore, MD
USA
b
Department of Oncology; The Johns Hopkins University School of Medicine, Baltimore, MD
USA
c
Department of Institute for Cellular Engineering; The Johns Hopkins University School of
Medicine, Baltimore, MD USA
Accepted author version posted online: 18 Mar 2015.
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To cite this article: Lingling Xian, Carol Ann Huff & Ms Linda Resar (2015): IBRUTinib: BRUTe Force against BortezomibResistant Myeloma Cells, Cell Cycle
To link to this article: http://dx.doi.org/10.1080/15384101.2015.1022058
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IBRUTinib: BRUTe Force against Bortezomib-Resistant Myeloma Cells
Lingling Xian1, Carol Ann Huff2, and Linda MS Resar1,2,3,*
1
Department of Medicine; The Johns Hopkins University School of Medicine, Baltimore, MD USA;
Department of Oncology; The Johns Hopkins University School of Medicine, Baltimore, MD USA;
3
Department of Institute for Cellular Engineering; The Johns Hopkins University School of Medicine,
Baltimore, MD USA;
2
*Corresponding Email: lresar@jhmi.edu
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Comment on: Murray MY, et al. Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome
bortezomib-resistance in multiple myeloma. Cell Cycle 2015.
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Multiple Myeloma (MM) is a clonal plasma cell dyscrasia that is currently incurable1-2. While
current therapy is effective at decreasing the tumor burden, or “debulking” the tumor, virtually all
patients ultimately relapse. The basis for relapse is incompletely understood, although global
genomic studies suggest that MM tumors are genetically heterogenous, both between patients and
within a single tumor1. Thus, relapse could occur through selection of a clone present at diagnosis,
which later expands because it can circumvent therapy. Another possibility is that a relapse clone
could evolve during therapy and expand because it harbors genetic or epigenetic mechanisms to
resist treatment. Alternatively, or perhaps in conjunction with clonal evolution, a clone of stem-like
cells or “cancer stem cells (CSCs)” that was relatively quiescent at presentation could emerge and
begin to proliferate after exposure to therapy that eradicates the more differentiated, “bulk” tumor
cells. This latter mechanism, or CSC theory, posits that a rare population of less-differentiated,
refractory CSCs (“tumor-initiator cells”) initiates and maintains the tumor3. Emerging evidence
suggests that master regulators, such as the high mobility group A1 (HMGA1) chromatin remodeling
protein, orchestrates the assembly of Nuclear–factor kappa B (NF-κB) and transcription factor
complexes to induce stem cell transcriptional networks and downstream signaling pathways that
maintain CSCs3-6. Prior studies also suggest that Nuclear–factor kappa B (NF-κB) is hyperactive in MM
and leukemic stem cells (Fig. 1)1,7. Regardless of the basis for chemoresistance, successful MM
treatment hinges on the discovery of molecular pathways that mediate resistance and can be
targeted with therapy.
In the XX issue of Cell Cycle, Murray et al. report a critical first step in reaching this lofty goal, not
only in elucidating molecular underpinnings of resistant disease, but also in effectively targeting
resistance mechanisms2. Treatment for MM includes combination therapy with corticosteroids or
cytotoxic agents along with the proteasome inhibitor, bortezomib1-2. As noted, NF-κB signaling is
up-regulated in MM, and bortezomib functions by inhibiting proteasomal degradation of the
endogenous NF-κB inhibitor, IκB (Fig. 1). While single agent therapy with bortezomib results in
remissions in only ~30% of patients, combination therapy has led to improved survival times and
remissions in up to 60-90% of patients1. Unfortunately, remissions are generally short-lived and most
patients succumb to MM within 5-10 years of diagnosis1-2.
In order to identify relapse-specific mechanisms that could be targeted, relapse was modeled in
vitro by selecting cultured MM cells resistant to bortezomib2. Resistance in MM has been attributed
to multiple factors, including increased NF-κB signaling, enhanced growth factor and/or oncogenic
signaling, mutated proteasome subunits, or deregulated plasma cell maturation markers1. In this
study, proteasome activity was assessed using a functional assay and found to be increased in
resistant cells. Bortezomib resulted in cytotoxicity in MM cells from naïve (untreated) patients, while
most resistant cells (4/6) were unaffected. Because Bruton’s tyrosine kinase (BTK) activity can induce
NF-κB activity, it was assessed and found to be highest in resistant cells. Following bortezomib, BTK
activity decreased in sensitive cells, although there was no change in resistant cells, suggesting that
BTK could be critical for bortezomib resistance. To investigate this further, BTK promoter activity,
which includes 2 NF-κB binding sites, was assessed and up-regulated in resistant clones. Moreover,
BTK promoter was repressed by bortezomib in sensitive cell lines, but not in resistant cells. To
determine whether BTK could be targeted, resistant MM cells were treated with the BTK inhibitor,
ibrutinib, which resulted in cytotoxicity. When ibrutinib was administered with bortezomib, cell
2
viability decreased further, and was dependent upon BTK. Finally, this study revealed that BTK
induction was dependent upon the p65/RelA subunit of NF-κB. Together, this compelling work
suggests that iBRUTinib could provide “brute force” needed to re-sensitize resistant MM clones to
bortezomib and may help to eradicate relapsed disease (Fig. 1).
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In summary, this well-orchestrated study provides an elegant example of how elucidating
molecular underpinnings of resistant disease may lead to more effective therapies. Clinical studies
are needed to translate these results into effective therapy. This study also underscores the
importance of p65/ReA and NF-κB signaling in relapsed MM and reveals another potential
therapeutic target. Targeting chromatin remodeling proteins that recruit NF-κB to DNA could also
prove to be an important adjunctive therapy in relapsed MM3-4.
3
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References
1. Murray MY, et al. Biochem Soc Trans. 2014; 42:804-808.
2. Murray MY, et al. Cell Cycle. 2015; Jan 7:0. [Epub ahead of print]
3. Yanagisawa B et al. Expert Rev Anticancer Ther 2014; 14:23-30.
4. Resar LMS. Cancer Res 2010; 70:436-439.
5. Schuldenfrei A, et al. BMC Genomics 2011; 12:549.
6. Shah SN, et al. PLoS ONE 2013; 8:e63419.
7. Kuo H-P, et al. Cancer Cell 2013; 24:423-437.
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Figure Legend: Signaling pathways in MM. Hyperactive NF-κB induces pro-survival genes after: 1)
phosphorylation of p65, 2) proteosomal degradation of IκB. In sensitive clones, bortezomib inhibits
NF-κB activity by blocking proteasomal degradation of IκB. In resistant clones, bortezomib induces
phosphorylation of IKKβ and IκB, leading to non-proteosomal degradation of IκB. Ibrutinib can
overcome this mechanism by repressing BTK, which results in inactive p65 and NF-κB.
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