Dissecting and targeting a novel vulnerability in Rb1 and p53 doubly deficient prostate cancer
Prostate cancer is the second most common cancer in men worldwide and the second leading cause of cancer
death in American men. Rb1 and p53 are two prototypical tumor suppressors. Loss of one or both alleles of
either gene leads to significant deficiency in its functions, which contributes to the oncogenesis and progression
of human cancers, including prostate cancer (PCa). Concurrent Rb1 and P53 Deficiency (RPD) is common in
PCa cases that are aggressive and have poor prognosis. The mechanisms of increased cancer mortality in RPD-
PCa are far from well understood, which has hindered the development of effective treatments. Our goal is to
investigate the mechanisms underlying RPD PCa progression and to target novel vulnerabilities of RPD-
PCa cells. We have found that GPCR-kinase 3 (GRK3) is expressed significantly higher in RPD-PCa than in
non-RPD-PCa. In line with this, GRK3 expression correlates with Rb1-loss or p53-loss gene signatures. Using
the genetic and pharmacological tools that we have acquired to modulate GRK3, we have begun to gain critical
insights into the mechanisms of GRK3 and RPD in PCa. We have identified a key epigenetic regulator that is
activated by GRK3 as its kinase substrate. Our preliminary data show that GRK3 silencing preferentially ablates
RPD-PCa cells, and that its knockout inhibits PCa progression and extend survival of the TRAMP mice, a RPD-
related genetically engineered mouse (GEM) model. Our overarching hypothesis based on these results is
that GRK3 is essential for the molecular mechanisms and the fitness of RPD-PCa cells, and that GRK3
signaling through its substrates is a vital part of the mechanisms of RPD aggressiveness. To target GRK3
and to dissect molecular mechanisms underlying its function in RPD cells, we have carried out compound library
screens and identified two potent and first-in-class GRK3 inhibitors which effectively block GRK3 activity and
preferentially ablate RPD-PCa cells. We also hypothesize that blocking GRK3 with these inhibitors will
thwart RPD tumor growth and metastasis. To test these hypotheses, we propose to pursue three Aims: 1.
validate GRK3 as a novel vulnerability in RPD-PCa by examining the effects of its silencing in xenograft models
and its knockout in a genetically defined RPD GEM model; 2. determine the impact of GRK3 inhibitors on the
properties of RPD-PCa cells, as well as on the cancer progression in RPD-PCa cell-derived and patient-derived
xenograft models; 3. dissect the molecular mechanisms underlying GRK3-mediated aggressiveness in RPD.
Completion of these works is expected to establish a novel kinase-substrate relationship underlying RPD biology
and define GRK3 as an Achilles heel of RPD-PCa. It will also validate targeting GRK3 as a new direction for
developing effective therapeutics for lethal PCa. Our findings will have an impact on our understandings and
targeting of other aggressive cancer types where RPD is common.