Role of Androgen Receptor in Telomere Stability: A Novel Therapeutic Strategy in Potentiating AR-Targeted Therapies for the Treatment of Prostate Cancer
Abstract
The androgen receptor (AR) plays a critical role in proliferation and survival of prostate cancer (PCa), even castration-resistant PCa (CRPC). Yet, current treatments that aim to inactivate AR function (even second-generation drugs like enzalutamide that may benefit some CRPC patients) are not curative. A more complete understanding of the role of AR in PCa cell survival is needed to reveal new ways to kill PCa cells. Our studies address this need, as they point to the presence of a subset of AR in telomeres of PCa cells, a novel role of AR in telomere stability, a role of AR that is independent of AR transcriptional activity, and a role that can be exploited to enhance the effectiveness of AR antagonists for the treatment of CRPC in vivo. Telomeres protect chromosome ends from fusing to each other and thereby maintain genome stability. When such protection is lost (an event referred to as telomere dysfunction), chromosome ends are recognized as lesions by the DNA damage machinery. This results in the activation of a DNA damage response (DDR) at the telomeres. This DDR is characterized by activation of ATM, which in turn leads to activation of Chk2, a cell cycle checkpoint protein. Activation of this checkpoint control results in cell cycle arrest; this provides time to repair damage. If unprotected telomeres fuse with each other (a process referred to as ?repair?), the cell may resume mitosis. However, fused chromosomes will prevent equal distribution of the genome to daughter cells, and the pulling of paired centromeres to opposite mitotic spindle poles will lead to intra-chromosomal breakage. Continued cell cycling will lead to genome instability. Notably, checkpoint-mediated cell cycle arrest can be blocked by treating with an ATM inhibitor; this allows the cell to enter mitosis with damaged telomeres; the more damage, the more likely the cell will activate a cell death pathway. We discovered that AR antagonist treatment of PCa cells induces telomere dysfunction, activates a telomere DDR, and activates checkpoint control, even in CRPC cells that are not growth inhibited by AR antagonist. That led us to test the effect of an ATM inhibitor to block activation of the checkpoint control. Indeed, when we treated CRPC cells with AR antagonist plus ATM inhibitor, we induced significant and substantial cell death. Our goal in this proposal is to test the effectiveness of this drug combination on human CRPC tumors in vivo in mice. There is a growing realization that patient-derived xenograft (PDX) models that are serially transplantable in immunocompromised male mice may be good in vivo models to translate cell culture findings into clinical application. In Aim 1, we will use four different castrate-resistant PDX (CR PDX) models to test our hypothesis that combined treatment with AR antagonist plus ATM inhibitor is a new way to kill CRPC tumors in vivo. In addition, we will use an androgen-sensitive PDX model that involutes after castration but subsequently recurs, to test our hypothesis that our combination therapy approach will prevent recurrence to CRPC. We discovered that CRPC cells that resist growth inhibition by AR antagonist and survive AR antagonist-induced telomere dysfunction contain telomere aberrations. As telomere aberrations may underlie the development of genome instability, we hypothesize that treatment of CRPC cells with AR antagonist alone may do more harm than good by increasing genome instability. We will test this hypothesis in Aim 2. We will measure markers of genome instability (fusion of unprotected telomeres; and copy number alterations, the result of unequal distribution of fused chromatids to daughter cells) in CRPC cells treated with vs. without AR antagonist under in vitro and in vivo conditions. In addition, we will use an androgen-sensitive PDX model to determine whether an increase in telomere fusions and copy number alterations underlie the progression of androgen-sens
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710305
Entities
People
- Sahn-ho Kim
Organizations
- Henry Ford Health
- United States Army