RCC. Cyclin D1 binds the CDK4/6 kinases resulting in phosphorylation
and inactivation of the retinoblastoma (RB)
protein, with subsequent progression through the cell
cycle.102 Of note, RB loss is an uncommon event in ccRCC,
and thus cell cycle progression likely remains CDK4/6 dependent.
The CDK4/6 inhibitor palbociclib demonstrated a
G0/G1 cell-cycle arrest, induction of late apoptosis, and blockade
of RB phosphorylation in multiple RCC cell lines.103
Abemaciclib, another inhibitor of the CDK4/6 enzyme, was
shown to diminish tumor growth in combination with sunitinib
in mouse tumorgraft models,104 and a phase I trial
of the combination is now actively recruiting (NCT03
905889). Recently, Nicholson and colleagues demonstrated
synthetic lethality between CKD4/6 and VHL in ccRCC cell
lines as well as in a Drosophila model, suggesting a fundamental
dependency between these two gene products.105
Furthermore, the anti-proliferative effects of CDK4/6 inhibition
were synergistic with HIF-2 inhibition in mouse xenograft
models of disease,105 suggesting the combination of
CKD4/6 inhibitors with the HIF-2 antagonists described
above may also have therapeutic potential.
Another emerging strategy is to target the NRF2 pathway.
As previously alluded to, NRF2 is negatively regulated
by KEAP1, and under conditions of oxidative stress KEAP1
is bound by p62 releasing NRF2 to localize in the nucleus
and bind ARE. The NRF2/ARE pathway regulates a number
of genes involved in oxidative stress regulation, drug metabolism,
and cell proliferation.106 Among other functions,
NRF2 plays a vital role in overcoming oxidative stress and
treatment resistance. Accordingly, overexpression of NRF2
has been implicated as a negative prognostic marker in several
tumor types.107 Overexpression of NRF2/ARE-controlled
genes are a distinguishing feature of type II pRCC,48 and
elevated expression of NQO1 is associated with worsened
outcomes.48 Activating mutations in ccRCC are less frequent
than type II pRCC, however, emerging evidence suggests
epigenetic silencing of KEAP1 may contribute to
NRF2/ARE deregulation in ccRCC.108 Consistent with a potential
role of NRF2/ARE in ccRCC, NRF2 depletion via
shRNA was recently shown to decrease proliferation and increase
sensitivity to sunitinib in the 786-O ccRCC cell
line.109 Several flavonoids have been demonstrated to have
non-specific NRF2 inhibition, possibly through stimulating
polyubiquitination of NRF2.107 Direct inhibitors of NRF2
via the KEAP1 binding domains are also in development,106,
110.
Conclusion
Next generation sequencing has provided unprecedented
insight into the biology of RCC. The field has moved dramatically
from the discovery of the VHL gene by genetic
linkage analysis to the simultaneous and comprehensive
analysis of genomic, transcriptomic, metabolomics, and
proteomic data across multiple regions of a single tumor.
Novel bioinformatic strategies and insightful experimental
designs are revealing new molecular profiles of tumors and
the tumor microenvironment. The culmination of these
technologies has already resulted in refined prognostic opportunities
based on molecular, pathological, and clinical
variables. We are now rapidly shifting towards developing
and validating predictive models with the ultimate goal to
deliver on precision medicine.
102 Kidney Cancer Journal
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