http://jkcvhl.com
Journal of Kidney Cancer
and VHL 2014;1(1):1-11
Centre for Kidney Disease Research, School of Medicine, The
University of Queensland at Translational Research Institute, Brisbane,
Queensland 4102, Australia
Author for
correspondence: Christudas Morais, Centre
for Kidney Disease Research, University of Queensland at Translational Research
Institute, 37 Kent Street, Woolloongabba, QLD 4102, Australia, Email: [email protected]
Received: 11 March 2014; Accepted: 10 April 2014; Published 22 April 2014
Abstract
Of
the many targeted therapies introduced since 2006, sunitinib has carved its way
to become the most commonly used first-line therapy for the treatment of
metastatic renal cell carcinoma (RCC). Despite significant improvements in
progression-free survival, 30% of the patients are intrinsically resistant to
sunitinib and the remaining 70% who respond initially will eventually become
resistant in 6–15 months. While the molecular mechanisms of acquired resistance
to sunitinib have been unravelling at a rapid rate, the mechanisms of intrinsic
resistance remain elusive. Combination therapy, sunitinib rechallenge and
sequential therapy have been investigated as means to overcome resistance to
sunitinib. Of these, sequential therapy appears to be the most promising
strategy. This mini review summarises our emerging understanding of the
molecular mechanisms, and the strategies employed to overcome sunitinib
resistance.
Introduction
The role of VEGF in RCC
The role of mTOR in RCC
Targeted therapy in RCC
Elucidation of these
pathways had identified the potential of angiogenesis inhibition as a promising
therapeutic option for metastatic RCC leading to the development and
implementation of angiogenesis and mTOR inhibitors in clinical practice. These
targeted therapies are broadly classified as VEGF inhibitors, multi-tyrosine
kinase inhibitors and mTOR inhibitors. The most successful VEGF inhibitor is the
humanized VEGF-neutralizing antibody bevacizumab, which exerts its anti-angiogenic
activity by acting against the angiogenic endothelial cells surrounding the
tumor, rather than the tumor per se, thus blocking the supply of oxygen and nutrients to the tumors
(46-48). The multi-tyrosine kinase
inhibitors are sunitinib, sorafenib, pazopanib and axitinib. Many more are in
various phases of clinical trials. They inhibit multiple tyrosine kinase
receptors and neutralize the downstream signalling pathways activated by
ligand-receptor binding that leads to angiogenesis. Two of the most successful
mTOR inhibitors are temsirolimus and everolimus. Both are rapamycin analogues
and bind to FK506-binding protein 12 (FKBP12), which in turn binds to mTOR
leading to the inhibition of the PI3K/Akt/mTOR pathway (45, 49). In addition, temsirolimus has been shown to have a direct
inhibitory effect on HIF and VEGF (50). Of these targeted therapeutics, sunitinib
has become the most frequently used first-line targeted therapeutic for the
treatment of metastatic RCC.
Sunitinib in RCC
Table 1. Emerging mechanisms of resistance to sunitinib
Parameter |
Mechanism of Resistance |
Ref |
ATX* |
Endothelial ATX activates LPA signalling to promote renal tumorigenesis |
(64) |
Chemokines |
Down-regulation of angiostatic chemokines IFN-γ, IFN-γR and CXCL9
restores angiogenesis |
(65) |
COX-2* |
Enhanced COX-2 up-regulates HIF |
(66) |
EMMPRIN |
High EMMPRIN causes resistance via hyaluronan-mediated activation of
ErbB2 |
(67) |
HDM2/HDMX |
Inhibition of p53 by HDM2 and HDMX restores
angiogenesis |
(68) |
IL-8 |
Increased plasma level leads to tumor growth and
vascularity |
(69) |
Lysosomes |
Sequestration of sunitinib in lysosomes reduces
bioavailability |
(70) |
MicroRNA |
Decreased miR-141promotes angiogenesis; increased miR-942, miR-628-5p, miR-133a, and miR-484 promote
angiogenesis through up-regulation of MMP-9 and VEGF |
(71, 72) |
MDSC |
Intra-tumoral MDSC provides sustained immune
suppression and angiogenesis |
(73) |
NGAL |
Increased NGAL activates alternate pro-angiogenic
signaling pathway such as Ras-GTP, Erk1/2, and STAT1α |
(74) |
Polymorphism |
CYP3A5
rs776746; VEGFR2 rs1870377; VEGFR3 rs307826; VEGFR3 rs307821; VEGFR3
rs448012; PDGFRA rs1800812; IL-8 rs4073; PXR rs3814055; ABCB1 rs2032582;
ABCB1 rs1128503 |
(75-78) |
PRKX |
Overexpression up-regulates microphthalmia-associated transcription
factor (MITF) |
(79) |
PTEN |
Inactivation of PTEN restores angiogenesis through activation
of P13/Akt/mTOR |
(80) |
RLIP76 |
Active efflux of sunitinib from cells leads to reduced bioavailability |
(81) |
SKI |
SK1activates ERK and inhibits ATP-binding cassette
(ABC) drug transporter family |
(82) |
While the mechanisms of
sunitinib-mediated alternate angiogenesis are still elusive, hypoxia is
emerging as the major culprit. Sunitinib inhibits angiogenesis, largely through
the inhibition of VEGF and its receptors. This helps in the stabilization or
regression of the tumor in the short term. However, this also results in
hypoxia. Sustained hypoxia by sunitinib ‘resets’ the tumor microenvironment and
leads to the development of a VEGF/VEGFR-independent alternate angiogenic
pathway through the up-regulation of angiogenic factors other than VEGF (60, 83). For example, as shown in Table 1,
up-regulation of IL-8 or down-regulation of IFN-γ (65,
69), may circumvent the anti-angiogenic effects of sunitinib, and
functionally compensate for the VEGF/VEGFR-mediated inhibition of angiogenesis. Apart from contributing to acquired resistance through
alternate angiogenesis pathways, hypoxia could also contribute to intrinsic
resistance by selecting a more malignant RCC phenotype, which may accelerate
metastatic development and prone cells to insensitivity for anti-angiogenic
treatment (59, 84).
The pre-clinical studies (Table 1) have demonstrated the beneficial effects of adjunct therapy, targeted at the specific molecules identified at each study, to overcome resistance. However, their clinical relevance needs to be established. In patients, sunitinib rechallenge, combination therapy and sequential therapy have been investigated to overcome sunitinib resistance.
The rationale for
sunitinib rechallenge is that resistance to sunitinib is transient and that
after a short treatment interruption, sensitivity to sunitinib can be restored
by subsequent rechallenge. Evidence for this comes from a pre-clinical study, a
retrospective study, and a case report. In the pre-clinical study, primary RCC
cells isolated from patients who were resistant to sunitinib, when grown as a
mouse xenograft, responded to sunitinib (85). In
the retrospective study, of the 23 patients rechallenged with sunitinib, 5 patients (22%) achieved an objective partial response, and
17 patients (74%) had stable disease (86). The median progression-free survival (PFS) was 13.7
months with initial treatment, and 7.2 months with rechallenge. Patients who
had an interval of more than 6 months between sunitinib rechallenge had a longer PFS than those who started the
rechallenge within 6 months (median PFS, 16.5 vs 6.0 months; P=.03). No
substantial new toxicity or significantly increased severity of prior toxicity
was seen during rechallenge (86). A case report by Ravaud and colleagues showed that
rechallenge with sunitinib resulted in a partial response for 12 months in a
60-year old patient (61). Additional prospective studies are required to establish
the beneficial effect of sunitinib rechallenge.
Intrinsic and extrinsic
resistance to sunitinib remains a challenge in the effective treatment of
metastatic RCC. The mechanisms of intrinsic resistance remain elusive, and much
research is warranted in this largely unexplored area. At the same time,
pre-clinical studies have been unravelling the molecular mechanisms of
extrinsic or acquired resistance at a rapid rate. However, there is a wide gap
between the bench and the bedside. While optimism remains that this gap will
narrow in the years to come, at present, the best strategy to overcome
resistance to sunitinib appears to be sequential therapy. There is no universal
consensus as to the optimal sequence of therapy. While establishing a universal
consensus for sequential therapy appears logical, the practicality of
implementing such approach would be difficult, at least in part, due the
heterogeneity of RCC. Thus personalised medicine could be one way to overcome
resistance. To achieve this, discovery of a sunitinib resistance ‘biomarker
map’ would be of utmost value. A close interaction between clinicians and basic
scientists aimed at designing clinically relevant experiments will enable a
speedy resolution to overcome sunitinib resistance in the days to come.
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