Date Published: May 13, 2019
Publisher: Public Library of Science
Author(s): Vidyavathi Reddy, Asm Iskander, Clara Hwang, George Divine, Mani Menon, Evelyn R. Barrack, G. Prem-Veer Reddy, Sahn-Ho Kim, Lucia R. Languino.
Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice variant AR-V7, but full-length AR was found to be the predominant form of AR associated with telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this combined treatment approach to induce telomere DNA damage and inhibit the DDR was effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express AR splice variant.
The critical role of the androgen receptor (AR) in prostate cancer cell proliferation and survival is the enduring basis for treating advanced prostate cancer with drugs that block AR function or androgen biosynthesis [1, 2]. However, a relentless challenge is the development of resistance to these treatments, referred to as castration-resistant prostate cancer (CRPC) . Remarkably, CRPC still relies on AR [4, 5], indicating a need to more fully understand the role of AR in cell survival. In this regard, we have discovered a role of AR in prostate cancer cell telomere stability [6, 7]. Notably, inactivation of this role of AR creates a DNA damage response (DDR) target, inactivation of which blocks repair and promotes cell death .
The expression of constitutively active AR splice variants such as AR-V7, which lacks the ligand binding domain, is considered an important mechanism of AR antagonist-resistant growth of metastatic CRPC [15, 17]. However, because full-length AR is expressed in 80–100% of AR-positive CRPC metastases [18, 45], and because full-length AR, not AR-V7, is associated with telomeres and is critical for telomere stability, CRPC metastases are expected to be vulnerable to telomere DNA damage by AR antagonist, and activation of a telomere DDR that can be inhibited by an ATMi to promote cell death, as demonstrated in CRPC 22Rv1 cells and tumors, and in CRPC cell lines C4-2B and LNCaP/AR (this study). Combined treatment with ENZ plus ATMi suppressed tumor growth (Fig 5A and S3 Fig) and increased cell death (Fig 5E), presumably a result of ATMi blocking DNA repair in cells with a DDR and activated pATM, so that cells with too much damage undergo cell death [8, 14, 46].