International Journal of Myeloma 6(1): 1–6, 2016
©Japanese Society of Myeloma

REVIEW

Mechanism of action of bortezomib in multiple myeloma therapy
Masaki RI1
A proteasome inhibitor, bortezomib (BTZ), was initially reported as an inhibitor of the NF-κB pathway, which plays acritical role in the pathogenesis of multiple myeloma (MM). The NF-κB activity of MM cells is mediated via two
distinguishable pathways, canonical and non-canonical, which showed opposing action after BTZ treatment in MM
cells. Recent studies of proteasome inhibition in MM cells reveal that accumulation of unfolded proteins in theendoplasmic reticulum (ER), so called ER stress, triggered several pro-apoptotic factors and cell stress such as
Reactive Oxygen Species (ROS) accumulation, which is considered to be the main mechanism of action of BTZinduced apoptosis. Several factors associated with ER stress and unfolded protein response (UPR), have been identified with sensitivity of BTZ treatment. Low levels of XBP1, ATF3, and ATF4, which regulate UPR and ER stress-induced
apoptosis, have been observed in poor responders to BTZ treatment, and three other genes, KLF9, Nampt, andCDK5, are associated with response to BTZ-containing therapy. These findings contribute to a better understandingof the mechanism of BTZ-induced apoptosis in MM cells, and further study is needed to develop potential predictive
biomarkers of efficacy of BTZ-containing therapy.
Key words:

bortezomib, multiple myeloma, mechanism of action, ER stress, NF-κB

Introduction

and the change of administration route from intravenous tosubcutaneous, which enable long-term, steady treatment

Complete remission (CR) or very good partial remission

with BTZ.

(VGPR) has been observed in multiple myeloma (MM) therapy

Although most MM patients receiving continuous BTZ-

following the clinical use of the proteasome inhibitor,

containing­therapy do not develop severe adverse events, the­bortezomib (BTZ), which has markedly improved the treat-number of cases with acquired resistance to BTZ therapy has

ment outcome of MM in Japan 1). Although several adverse

increased currently. Several clinical studies of BTZ treatment

events, such as peripheral neuropathy and severe constipa-

for relapsed or refractory (RR) MM showed that the mediantion, occurred during the treatment, BTZ is now widely used in

duration of response ranged from half-year to a year with or

the treatment of MM as initial therapy or in relapsed/refractory­

without dexamethasone, which supports the theory that incases and in transplant eligible or non-eligible patients. During

most of cases of continuous BTZ treatment, MM eventually

the early stage of clinical use, early discontinuation of thisacquired BTZ resistance within a year 3). To explore effective

agent often occurred owing to adverse events such as severe

treatment strategy for overcoming BTZ resistance, several

peripheral neuropathy and gastrointestinal disorders. How-

clinical trials using new agents or combination therapy with

ever, owing to accumulation of clinical experience, appropriate

BTZ have been performed on RR MM cases pre-treated withmethods of administrating this agent have been established,

BTZ. However, little is currently known about the mechanism

such as early-dose reduction, once-weekly administration 2),of acquired resistance to BTZ; therefore, these trials were notalways planned to target the mechanism of action of BTZ

Received: July 22, 2015, accepted: July 26, 2015
1
Department of Hematology and Oncology, Nagoya City University
Graduate School of Medical Sciences
Corresponding author: Masaki RI, M.D., Ph.D.
Department of Hematology and Oncology, Nagoya City University
Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-chou,Mizuho-ku, Nagoya, Aichi 467-8601, Japan
TEL: 81-52-853-8738, FAX: 81-52-853-8740
E-mail: rrmasaki@ybb.ne.jp

resistance in MM cases. To develop an effective treatment
strategy, it is essential to address the mechanism of action of
BTZ-induced anti-tumor effect, to determine how tumor cells
acquire resistance to the agent and to develop an optimal
therapy targeting the specific pathway attributable to drug
resistance. In this review, we summarize recent knowledgeof the mechanism of BTZ-induced cell death and the factors
associated with sensitivity to BTZ treatment by reviewing­previous reports on preclinical and clinical studies of MM.

International Journal of Myeloma

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Role of Ubiquitin-Proteasome Pathway
in Malignant Tumor Cells

thesis, adequate folding, glycosylation, and transport of newly
generated proteins. To regenerate the misfolded proteins, MM
cells have highly developed Endoplasmic-reticulum-associated

The ubiquitin-proteasome system plays a crucial role inprotein degradation (ERAD) systems, by which misfolded

maintaining intracellular homeostasis, regulating substrates­proteins are excluded from the ER, conjugated by polyubiq­

that control cell cycle, metabolism, survival, and apoptosis,

uitination, and subjected to proteolysis at the proteasome.

and eliminating damaged proteins that are toxic to the cells.

Therefore, the inhibition of proteasomes would contribute

In eukaryotic cell, substrates to be degraded are conjugatedto a disruption in the balance of the ERAD system, followedby polyubiquitination via E2 and E3 ligase, subsequently lead-by an over-stress of the ER and sequential progression of

ing to their degradation by 20S proteasome. In general, tumor

apoptosis in MM cells.

cells have a more developed proteasome pathway than normal cells 4), because tumor cells have an abundant capability
for synthesis, movement, and modification of proteins, owing

Main Mechanism of Action of Proteasome
Inhibition in MM Cells

to their advanced cell proliferation and highly activated invasion into other organs. To compensate for the stress generated

BTZ is a boronic acid dipeptide that inhibits activations ofby marked synthesis and modification of proteins, tumor cells

β5 and β1 subunits of the 20S proteasome core in the 26S pro-depend on the proteasome pathway, where misfolded proteinsteasome complex, and is characterized as a reversible inhibitorand functional proteins are uniformly degraded and remoldedof the above activities 6). Misfolded proteins and functional

effectively 5). Of the several tumor cell types, MM cells andproteins to be degraded by the proteasome accumulate in thepancreatic­tumor cells, which contain many secreted proteins,

ER lumen and cytosol via this mechanism. This accumulation

are more dependent on the ubiquitin-proteasome pathway. In

facilitates several stresses, including ER overload, the genera-

the case of MM cells, unfolded proteins, including monoclonaltion of excess oxygen, and a functional disorder of intracellularimmunoglobulin and various cytokines critical for maintaining

proteins, eventually leading to ER stress-related apoptosis 7,8)

the interaction of stroma cells, easily accumulate during syn-and cell death due to the DNA damage 9,10) (Fig. 1).

Figure 1. Effects of proteasome inhibition on multiple myeloma cells. Inhibition of proteasome action by bortezomib (BTZ) treatment results inaccumulation of misfolded proteins and functional proteins to be degraded by the proteasome in the endoplasmic reticulum (ER) lumen andcytosol, which facilitates several stresses, including ER overload, generation of excess oxygen, and functional disorder of intracellular
proteins, eventually leading to ER stress-related apoptosis and cell death due to DNA damage. BTZ also disrupts the paracrine growth ofmultiple myeloma (MM) cells in the bone marrow (BM) milieu by inhibiting MM cell interaction with BM stroma cells (BMSC) through the
suppression of cell adhesion molecules, such as VLA-4, in the MM cells and the secretion of IL-6 and IGF-1 in the BMSC cells.

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vol. 6 no. 1 (2016)

Mechanism of action of bortezomib

Newly synthesized proteins, secretory proteins, such asphorylated by IκB kinase (IKK) and subsequently polyubiquiti-

cytokines, chemokines, and immunoglobulin, are transported

nated and degraded by the 26S proteasome, which promotes

to the ER, folded with adequate conformation by ER chaper-

the translocation of RelA and the p50 complex. When inhibi-ones, and modified as mature proteins by the addition of ation of proteasome occurs owing to BTZ administration, phos-

complicated structure of glycoproteins at the ER and Golgi

phorylated IκB accumulates in the cytosol and prevents the

body. However, when the misfolding is too severe, the proteinstranslocation of RelA and the p50 complex, thereby suppress-

are removed from the ER, added to the cytosol via polyubiqui-

ing canonical NF-κB activity. However, unlike earlier reported

tination by E2 and E3 ligase, degraded by proteasomes, andstudies, recent study shows that BTZ activates constitutive

subjected to ERAD. Therefore, inhibition of proteasomes

NF-κB activity in various tumor cell lines 16), suggesting therepresses the degradation and recycling of proteins and aminoneed for precise re-evaluation of BTZ activity on NF-κB activity

acids from the misfolded proteins, causing the accumulationin MM cells. Recently, Hideshima et al have shown that BTZof these misfolded proteins in the ER 11). The excess production

triggered an expected increase in the expression levels ofof immunoglobulin and several cytokines allows MM cells tophosphorylated IκBα and an unexpected downregulation ofmaintain contact with stroma cells in the bone marrow (BM)IκBα, followed by constitutive NF-κB activation mediated bymilieu. Therefore, MM cells can tolerate the excess ER stress

nuclear translocation of the p65 complex in MM cell lines 16).

because they have a well-developed ER compared with other

Although BTZ activates constitutive NF-κB activity, it is also

hematological malignant tumor cells. When proteasome

possible that BTZ blocks non-canonical NF-κB activity, because

action is inhibited, MM cells are easily exposed to uncompen-

inhibition of the proteasome-dependent conversion of p100

11)

sated ER stress , which facilitates the progression of cellto p53 is observed in BTZ-treated MM cell lines. Non-canonicaldeath rather than amelioration of cell stress by restoring

NF-κB activation is also involved in the main pathogenesis ofdamaged proteins. ER stress-induced apoptosis is mainly­

MM cells. A previous report demonstrated that non-canonicalcaused by an elevation in the levels of proapoptotic transcrip-

NF-κB activity was markedly elevated in primary MM cells

tional factor, C/EBP-homologous protein (CHOP), activation ofderived from patients 17), and elevation of this activity was

two caspase cascades, caspase 4 and 12, and phosphorylation­confirmed in BTZ-resistant primary MM cells from patients.

of c-Jun N-terminal protein kinases, which in turn advance the

Therefore, it should be considered that the alteration of NF-κB

caspase-dependent apoptosis of MM cells 11,12).

activity by BTZ depends on the cell type and dominant typeIn the process of remodeling proteins, Reactive Oxygen Spe-of NF-κB activity, canonical or non-canonical, in MM cells.

cies (ROS) have played a critical role in the adequate folding of
the protein complex 13). However, by proteasome inhibition,
unfolded proteins accumulate in the ER, which promotes the

Inhibition of the Interaction of MM Cells
with Bone Marrow Stroma Cells

overproduction of ROS in the ER, resulting in fatal cell stress.
Toxicity from overproduction of ROS is also known as a main

With the interaction of bone marrow stroma cells (BMSC)

downstream result of ER stress caused by proteasome in­via cell-to-cell contact or cytokine release, MM cells usually

hibition and is known as a main mechanism of BTZ-induced

acquire survival benefits from BMSC cells, such as cell prolif-

apoptosis of MM cells

14,15).

eration and resistance to therapeutic agents, so called celladhesion-mediated drug resistance (CAM-DR) (Fig. 1). BTZ

Inhibition or Activation of the NF-κB Pathway
in Proteasome Inhibition

treatment inhibited the expression of IL-6 receptor in MM
cells 18), which decreased the activation of IL-6-induced ERK,STAT3, and Akt pathways, and non-canonical NF-κB activity.

The mechanism of action expected in the clinical use of BTZ

With BTZ treatment, MM cells lost their expression of the IL-6

is an inhibitory effect on NF-κB activity in MM cells. NF-κB is a

receptor 18), which resulted in non-canonical NF-κB activity andcomplex with a dimer of different Rel families, including RelAin the decreased activation of the IL-6-induced ERK, STAT3,(p65), RelB, c-Rel, p50 (NF-κB1), and p52 (NF-κB2), and has an

and Akt pathways. BTZ treatment decreased the expression ofimportant role in the biology of several tumors. NF-κB activity

several cell adhesion molecules, such as VLA-4 19), on the MM

is composed of two different pathways, canonical and non-cell surface, disrupted the paracrine growth of MM cells in the

canonical. In the canonical pathway, a heterodimer of RelA andBM milieu, and decreased the secretion of IL-6 and IGF-1 in

p50 translocates into the nucleus and upregulates several sur-

BMSC cells, resulting in the suppression of the MM cell’s

vival genes (usually regulated by IκBα family proteins) throughadherence to BMSC, thereby enhancing MM cell susceptibility

transcription. Following several stimulations by various cyto-

to therapeutic agents.

kines such as IL-6, IGF-1, and TNF-α, the IκBα protein is phos-International Journal of Myeloma

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Figure 2. Two ATF genes are involved in the clinical outcome of patients with multiple myeloma receiving the bortezomib plus dexamethasone
therapy. A: Higher expression levels of ATF3 and ATF4 correlate with longer duration of response in 57 patients with relapsed/refractory
multiple myeloma (MM) treated with bortezomib and dexamethasone in Nagoya City University Hospital. Each bar represents the medianvalue of progression-free survival (PFS). Comparison of gene expression between two groups with longer and shorter PFS after bortezomib
plus dexamethasone therapy was made using the Mann–Whitney U test. In this study, P < 0.05 was considered significant. B: Higher
expression levels of both ATF3 and ATF4 are associated with longer PFS in patients with relapsed/refractory MM treated with bortezomib
plus dexamethasone. Survival analysis used the Kaplan-Meier estimate. In this study, P < 0.05 was considered significant.

Factors Associated with Bortezomib Sensitivity
in Myeloma Cells

identified CDK5, cyclin-dependent kinase 5 22). Since CDK5
upregulates the expression of the PSMB5 gene at a transcriptional level, MM cell lines with high expression of CDK5

Several studies have tried to determine the factors associ-showed low sensitivity to BTZ treatment compared to cell lines

ated with BTZ sensitivity in MM cells to establish new clinicalwith low expression. Furthermore, two reagents, Roscovitine

biomarkers, which will contribute to identifying patients who

and SCH727965, which have inhibitory effects on CDK5,

will benefit maximally from BTZ-containing therapy, or who

enhanced BTZ-induced apoptosis in MM cell lines. Recently,

will experience severe side effects, such as peripheral neuropa-

miR-27a-5p, suppressing the expression of CDK5 by inhibiting

thy and interstitial pneumonia when BTZ is administrated.

the translation of CDK5 and mRNA 23), has been reported to be

20)

In the APEX study , Mannava et al. have reported that the

downregulated during BTZ treatment, which result in the acti-

expression level of Kruppel-like factor 9 (KLF9) is involved invation of CDK5 following upregulation of PSMB5, considered

the response of BTZ-containing therapy for RR MM. In thisas the compensatory effect of stress in MM cells; therefore,

study, most patients with MM who showed a high level of KLF9

CDK5 inhibition enhances BTZ activity and has potential as aexpression in primary MM cells showed good response to BTZ

therapeutic option.

treatment compared to patients with low KLF9 expression.

Proteasome inhibition causes the accumulation of misfolded

KLF9 is upregulated by Histone Deacetylase inhibition induced

proteins; hence, it initiates ER stress followed by an unfoldedby BTZ treatment, and is associated with the transcriptional

protein response (UPR), which has crucial roles in the cytotoxic

factor attributable to Noxa gene expression; Noxa is a BH3-only

effect of PI. Thus, the magnitude of dependence on the protea-

protein that serves as a proapoptotic factor. In other reports,some and the UPR may affect MM cells’ sensitivity to PI. Ling etanalysis of plasma cells of patients with MM collected in theal. and Gambella et al. have reported that XBP1, a downstream

APEX study showed that a high expression level of nicotin-of activated IRE1 involved in UPR, is associated with the clini-amide phosphoribosyltransferase (Nampt) is associated with acal outcome of MM patients who received BTZ-containing

poor outcome of BTZ treatment, poor response to the treat-

therapy. In their reports, low expression of the XBP1 gene isment, and short duration of survival after the treatment 21).

observed in primary MM samples from patients who respond

Silencing of Nampt by the shRNA or HDAC inhibitor FK228,

poorly to bortezomib and dexamethasone (BD) treatment 24),

which suppresses Nampt expression by decreasing intracellu-

and high expression of XBP1 is defined as a good prognosis

lar NAD+ levels in MM cell lines, increased the sensitivity ofmarker of survival among patients receiving BTZ-containing

MM cells to BTZ treatment compared to control cells. Using

regimen 25). In our study, we investigated 57 patients with RR

siRNA screening analysis, Zhu et al investigated the specific

MM treated with BD in Nagoya City University Hospital (Fig.

factor that influences the sensitivity to BTZ treatment, and

2A, B). The expression levels of proteasome- and ER stress-

4International Journal of Myeloma

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Mechanism of action of bortezomib

related genes in primary tumor samples obtained prior to BD

References

treatment were evaluated in association with clinical outcomes. Among those, a couple of genes encoding for the ATF
family seemed to correlate with sensitivity to BTZ. We identified that the expression level of two ATF genes, ATF3 and ATF4,
was lower in the shorter PFS group (PFS < 6 months) than in
the longer PFS group (Fig. 2A). In addition, cut-off values of the
ATF3 and ATF4 expression level adjusted by the β-actin expression level were defined as 1.0 and 0.135, respectively, whichshowed that MM patients with high expression levels of both
ATF genes showed longer PFS than the other group harboring
low expression level of either gene, (median PFS: 9.0 vs 3.2
months) (Fig. 2B) 26). We speculate that MM cells with a highexpression of ATF genes pose the conventional ER stress, thus
proteasome inhibition by BTZ exposure could trigger further
ER overloads followed by an uncompensated ER cell stresseven with UPR activation and rapid apoptosis progression inthese cells. Previous reports and our recent study showed thatsuppression of ATF3 and ATF4 by an RNA-interfering method
has inhibited death receptor DR5 expression and the upregulation of Noxa, a proapoptotic BH3-only protein, by BTZ treatment in MM cells. Using chip analysis from MM cell lines andprimary MM samples from patients, we also confirmed thatthe complex of ATF3 and ATF4 works as a transcriptional factorof the Noxa gene. In summary, from the analysis of primarytumor samples from patients received BTZ-containing therapy,
KLF9, Nampt, CDK5, and 3 ER stress- and UPR- associatedmarkers (XBP1, ATF3, and AFT4), were identified as a predictive
markers of sensitivity of BTZ treatment. However, these factors
have not been fully evaluated, and it seems to be difficult toclearly predict the efficacy of BTZ treatment using a single
factor, owing to the heterogeneity and complexity of bioactivity in MM cells and the mechanism of action of BTZ-induced
cell death.

Conclusion
By the accumulation of studies of BTZ, the mechanism ofaction of the BTZ-induced effect on MM cells has emerged
gradually, with better understanding of not only NF-κB signaling but also ER stress and subsequently the URR system in MM
cells. In addition, several factors associated with BTZ sensitivity
have also been identified, which contribute to understanding
the differences in the biological activity of MM cells withrespect to their dependence on proteasome activity and UPR.
Further study of the mechanism of BTZ-induced activity isneeded to establish a well-characterized predictive marker of
BTZ response and to develop a potent treatment strategy forthis incurable disease.

1) Ogawa Y, Tobinai K, Ogura M, Ando K, Tsuchiya T, Kobayashi Y, etal. Phase I and II pharmacokinetic and pharmacodynamic study ofthe proteasome inhibitor bortezomib in Japanese patients withrelapsed or refractory multiple myeloma. Cancer Sci. 2008; 99:
140–4.
2) Tokuhira M, Watanabe R, Nemoto T, Hanzawa K, Sagawa M,
Tomikawa­T, et al. Successful treatment with a modified bort­
ezomib schedule of weekly and longer intervals for patients withrefractory/resistance multiple myeloma. Leuk Res. 2011; 35: 591–7.
3) Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson
PG, et al. A phase 2 study of two doses of bortezomib in relapsed
or refractory myeloma. Br J Haematol. 2004; 127: 165–72.
4) Adams J. The development of proteasome inhibitors as anticancer
drugs. Cancer Cell. 2004; 5: 417–21.
5) Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, SzomolanyiTsuda E, Gravallese EM, et al. Plasma cell differentiation requires
the transcription factor XBP-1. Nature. 2001; 412: 300–7.
6) Crawford LJ, Walker B, Ovaa H, Chauhan D, Anderson KC, Morris
TC, et al. Comparative selectivity and specificity of the proteasome inhibitors BzLLLCOCHO, PS-341, and MG-132. Cancer Res.
2006; 66: 6379–86.
7) Chauhan D, Hideshima T, Mitsiades C, Richardson P, Anderson KC.
Proteasome inhibitor therapy in multiple myeloma. Mol Cancer
Ther. 2005; 4: 686–92.
8) Ri M, Iida S, Ishida T, Ito A, Yano H, Inagaki A, et al. Bortezomibinduced apoptosis in mature T-cell lymphoma cells partiallydepends on upregulation of Noxa and functional repression of
Mcl-1. Cancer Sci. 2009; 100: 341–8.
9) Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D,
Richardson P, et al. Molecular mechanisms mediating anti­
myeloma activity of proteasome inhibitor PS-341. Blood. 2003;
101: 1530–4.
10) Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT,
Chauhan D, et al. The proteasome inhibitor PS-341 potentiates
sensitivity of multiple myeloma cells to conventional chemo­
therapeutic agents: therapeutic applications. Blood. 2003; 101:
2377–80.
11) Obeng EA, Carlson LM, Gutman DM, Harrington WJ, Jr., Lee KP,
Boise LH. Proteasome inhibitors induce a terminal unfolded­protein response in multiple myeloma cells. Blood. 2006; 107:
4907–16.
12) Yoshida H. ER stress and diseases. FEBS J. 2007; 274: 630–58.
13) Shimizu Y, Hendershot LM. Oxidative folding: cellular strategies
for dealing with the resultant equimolar production of reactive
oxygen species. Antioxid Redox Signal. 2009; 11: 2317–31.
14) Fribley A, Zeng Q, Wang CY. Proteasome inhibitor PS-341 induces
apoptosis through induction of endoplasmic reticulum stressreactive oxygen species in head and neck squamous cell carcinoma cells. Mol Cell Biol. 2004; 24: 9695–704.
15) Perez-Galan P, Roue G, Villamor N, Montserrat E, Campo E,
Colomer D. The proteasome inhibitor bortezomib induces
apoptosis­in mantle-cell lymphoma through generation of ROS
and Noxa activation independent of p53 status. Blood. 2006; 107:257–64.
16) Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, et al.
Bortezomib induces canonical nuclear factor-kappaB activation

International Journal of Myeloma

vol. 6 no. 1 (2016)

5

RI

in multiple myeloma cells. Blood. 2009; 114: 1046–52.
17) Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, et al.
Promiscuous mutations activate the noncanonical NF-kappaB­
pathway in multiple myeloma. Cancer Cell. 2007; 12: 131–44.
18) Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N,
Mitsiades C, et al. Proteasome inhibitor PS-341 abrogates IL-6
triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene. 2003; 22: 8386–
93.
19) Noborio-Hatano K, Kikuchi J, Takatoku M, Shimizu R, Wada T, Ueda
M, et al. Bortezomib overcomes cell-adhesion-mediated drug
resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene. 2009; 28: 231–42.
20) Mannava S, Zhuang D, Nair JR, Bansal R, Wawrzyniak JA, Zucker
SN, et al. KLF9 is a novel transcriptional regulator of bortezomiband LBH589-induced apoptosis in multiple myeloma cells. Blood.
2012; 119: 1450–8.
21) Cagnetta A, Cea M, Calimeri T, Acharya C, Fulciniti M, Tai YT, et al.
Intracellular NAD(+) depletion enhances bortezomib-induced
anti-myeloma activity. Blood. 2013; 122: 1243–55.
22) Zhu YX, Tiedemann R, Shi CX, Yin H, Schmidt JE, Bruins LA, et al.

6International Journal of Myeloma

vol. 6 no. 1 (2016)

RNAi screen of the druggable genome identifies modulators ofproteasome inhibitor sensitivity in myeloma including CDK5.
Blood. 2011; 117: 3847–57.
23) Ballabio E, Armesto M, Breeze CE, Manterola L, Arestin M, Tramonti
D, et al. Bortezomib action in multiple myeloma: microRNAmediated­synergy (and miR-27a/CDK5 driven sensitivity)? Blood
Cancer J. 2012; 2: e83.
24) Ling SC, Lau EK, Al-Shabeeb A, Nikolic A, Catalano A, Iland H, et al.
Response of myeloma to the proteasome inhibitor bortezomib iscorrelated with the unfolded protein response regulator XBP-1.
Haematologica. 2012; 97: 64–72.
25) Gambella M, Rocci A, Passera R, Gay F, Omede P, Crippa C, et al.
High XBP1 expression is a marker of better outcome in multiple
myeloma patients treated with bortezomib. Haematologica. 2014;
99: e14–6.
26) Narita T, Ri M, Masaki A, Mori F, Ito A, Kusumoto S, et al. Lower
expression of activating transcription factors 3 and 4 correlateswith shorter progression-free survival in multiple myeloma
patients receiving bortezomib plus dexamethasone therapy.
Blood Cancer J. 2015; 5: e373.