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[23]
molecule inhibitors of HIF-2α have also been developed . HIF-2α antagonism may theoretically provide
[24]
additional efficacy than VEGF inhibitors . Currently under investigation, PT2385, a direct HIF-2α inhibitor,
[9]
has shown favorable safety profile and activity in patients with previously treated advanced ccRCC . Additional
approved and investigational treatments for ccRCC will be discussed in the “Current Therapies” section.

EPIGENETIC AND CHROMATIN REGULATION PATHWAYS IN CCRCC
Though it plays a key role in the pathogenesis of ccRCC, VHL loss alone is not sufficient for ccRCC
development. Given the latency of ccRCC formation in human VHL syndrome and the inability to induce
[25]
ccRCC in VHL-deficient mice , ccRCC development requires additional genetic and/or epigenetic events
to occur. In order to characterize these driving events, several prevalent novel gene mutations have been
identified, including PBRM1, SETD2, and BAP1. Located on 3p21, these genes encode for tumor suppressor
[26]
chromatin- and histone- modifying proteins , and unlike VHL loss, PBRM1 , SETD2 , and BAP1 [27,28]
[27]
[27]
mutations are associated with more clinical progression of individual stages of ccRCC.
PBRM1
[29]
PBRM1 was first identified as the second most commonly mutated gene in ccRCC in 2010 . Confirmed
in subsequent large-scale genomics studies, PBRM1 mutations occur in about 40% of human ccRCC
cases [4,30] . PBRM1 encodes for protein BRG1-associated factor (BAF) 180, a critical subunit of the polybromo
[30]
BAF SWI/SNF chromatin remodeling complex . SWI/SNF chromatin remodeling complexes are large
macromolecular structures that mobilize nucleosome via ATP consumption, thereby modulating chromatin
structure to regulate vital cellular processes, including cell cycle, cell fate, cell death, metabolism, and DNA
[33]
repair [30-32] . Detected in about 20% of human cancers , mutations in SWI/SNF proteins and other epigenetic
[34]
regulators encompass a major class of cancer genes, demonstrating preferential enrichment by cancer type .
PBRM1, highly mutated in ccRCC, has been shown to play a critical role in the tumorigenesis of ccRCC.

Several studies have established the tumor suppressor role of PBRM1 via analysis of pre-neoplastic renal cells in
kidney-specific PBRM1- and VHL-deficient mouse models and in RCC cell lines A704 and 786-O in vitro [30,35] .
Mechanistically, genetically engineered mouse kidney cancer models demonstrated that PBRM1 functions to
prevent kidney tumor cell growth by restraining the self-propagating over-amplification of HIF1 signaling
by limiting the HIF1-STAT3 feed-forward loop [30,35] .

In the same PBRM1-/- VHL-/- mouse model study, a long latency period of > 6 months was observed,
[30]
again suggesting the involvement of an additional oncogenic event . Activation of the mechanistic
target of rapamycin complex 1 (mTORC1) pathway as the preferred third driver event was observed
[30]
in several in vivo studies [16,30] as well as in human ccRCC cases carrying VHL and PBRM1 mutations .
A key cellular complex, mTORC1 integrates nutrient and growth factor signaling to promote anabolic
[36]
metabolism, supporting tumor growth and invasion . REDD1, a transcriptional target of HIF1, suppresses
mTORC1 activity via activation of TSC1/TSC2, functioning as a tumor suppressor checkpoint that limits the
[37]
oncogenic potential of HIF1 . Thus, the activation of the mTORC1 pathway and abrogation of the intrinsic
tumor suppressing activity of REDD1 and TSC1/2 may act as the final step to ccRCC development.

Ample clinical evidence support the importance of mTORC1 activation in the pathobiology of human
[38]
[39]
ccRCC , and mTOR inhibitors provide known therapeutic benefit in the treatment of metastatic ccRCC .
Correspondingly, PBRM1 mutation has been associated with longer progression-free survival with
everolimus, an mTOR inhibitor, vs. wild-type PBRM1 (12.8 months vs. 5.5 months) [40,41] . Similarly, patients
carrying truncal mutations in the mTORC1 signaling pathway, including TSC1, TSC2, and mTOR, also
benefited from mTOR inhibition [42,43] . Therefore, both clinical and preclinical data support the importance
of loss of PBRM1 as the preferred second event and the activation of mTORC1 as the preferred second/third
driver event in ccRCC tumorigenesis following VHL inactivation.