Implications of VHL-HIF Pathway Dysregulation in Renal Cell
Carcinoma: Current Therapeutic Strategies and Challenges
Introduction
Kidney cancer is among the 10 most common cancers in
both men and women, leading to approximately 74,000
new cases and to more than 14,000 deaths annually in
United States alone.1 Early stage, localized renal cell carcinoma
(RCC) has a significant cure fraction and a survival
rate of 92%, whereas the treatment of late stage
recurrent metastatic RCC remains highly challenging,
with a minority of patients with metastatic RCC surviving
past 5 years.2 Given that RCC is chemo-resistant and
radiation-resistant, novel targeted therapies were required
for the prevention and management of advanced
and/or metastatic RCC.
Studies found that the majority of localized and advanced
clear cell RCCs (ccRCCs) are characterized by mutational
inactivation and allelic loss of the von
Hippel-Lindau (VHL) tumor-suppressor gene. 3 The
groundbreaking discoveries made by William G. Kaelin
Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza on the involvement
of the VHL gene in various fundamental
processes, including but not limited to sensing and
adapting to the changing oxygen environment eventually
led to the Nobel prize in physiology and medicine
in 2019. These key insights not only paved the way for
our understanding of a key factor in ccRCC tumorigenesis,
but also provided the basis for the development of
VHL-hypoxia pathway-targeted therapies that includes
tyrosine kinase inhibitors (TKIs) for treatment of RCC
and other diseases.
In this review, we outline key aspects of VHL-hypoxia
inducible factor (HIF) pathway and their impact on tumorigenesis
in VHL disease and sporadic ccRCC. We
then explore the current status and future challenges for
the RCC treatment landscape in the context of VHL loss
and other biological factors.
6 Kidney Cancer Journal
Implications of VHL Loss in VHL Disease
and Sporadic ccRCC
von Hippel-Lindau disease is a rare autosomal dominant
hereditary neoplastic disorder triggered by germline mutations
in the VHL tumor-suppressor gene with an incidence
of roughly 1 in 36,000 births.4 Individuals with
VHL disease are at increased risk of recurrent and bilateral
kidney cysts and ccRCC, as well as retinal, cerebellar
and spinal hemangioblastomas, pheochromocytomas,
pancreatic cysts, serous cystadenomas and neuroendocrine
tumors, endolymphatic sac tumors and epidymal
and round ligament cysts. 5 The discovery of the
VHL gene in 19936 was driven by a desire to understand
and treat VHL disease. The impact of this seminal discovery
on our understanding of disease manifestations
in patients with VHL disease and on individuals with
sporadic ccRCC cannot be overstated. We now know
that the majority of sporadic ccRCC cases also exhibit
somatic loss-of-function mutations in the VHL gene,3
loss of 3p chromosome, or hypermethylation of the VHL
locus.7,8
The mechanistic understanding of VHL protein
(pVHL) function, driven by Kaelin’s group and others
formed the cornerstone of our current understanding of
ccRCC biology. Through additional work performed by
a number of investigators and organizations including
The Cancer Genome Atlas (TCGA), we now know VHL
loss serves as the initiating truncal event for ccRCC tumorigenesis,
eventually followed by additional mutational
and chromosomal copy number altering changes
that foster tumor growth and lethality.8-11
The VHL- HIF Pathway
Bill Kaelin and colleagues were instrumental in characterizing
the VHL gene and its function. In 1995, Iliopoulos,
Kibel, Gray and Kaelin showed that the reintro-
duction of a wild-type but not a mutant VHL cDNA into
the 786-0 VHL(-/-) RCC cell line abrogated its ability to
form tumors in nude mouse xenograft assays, reinforcing
the concept that VHL is a bona fide tumor suppressor
gene.12 In the same year, the Kaelin group showed that
pVHL interacts with with elongins C and B to form the
Eric Jonasch, MD
Professor, Department of
Genitourinary Medical Oncology
Director, The Von Hippel Lindau
Clinical Center
The University of Texas MD Anderson
Cancer Center
Houston, TX
Keywords: renal cell carcinoma, VHL-HIF pathway, loss of VHL, HIFs
dysregulation, Mutational landscape of RCC, William Kaelin's discovery,
therapeutic targets
Corresponding Author: Eric Jonasch, MD, Department of Genitourinary
Medical Oncology, The University of Texas MD Anderson Cancer Center,
Houston, TX, USA. Email: ejonasch@mdanderson.org
link