Cotargeting Telomere Integrity and Repair of Telomere Damage for CRPC Therapy
Abstract
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. 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, indicating a need to more fully understand the role of AR in cell survival. Our studies address this need, as we have discovered a role of AR in prostate cancer cell telomere stability, and we have exploited it to kill CRPC cells. Telomeres are DNA-protein structures that cap the ends of chromosomes, protecting the DNA from being recognized by the DNA repair machinery of the cell as damaged DNA. Damaged telomeres elicit a DNA damage response (DDR) that leads to cell cycle arrest, when the cell can repair damage before entering mitosis. Repair thereby promotes cell viability. Conversely, blocking repair promotes cell death). We discovered that treatment of CRPC cells with AR inhibitor (ARi) leads to telomere DNA damage and activation of telomere DDR; moreover, inhibition of this DDR with an inhibitor of ATM (a specific component of this DDR signaling pathway) blocks the repair of damaged telomeres and causes cell death. Thus, we found that combined treatment of CRPC 22Rv1 cells in vitro or tumors in vivo with ARi and ATM inhibitor (ATMi), which target telomere integrity and repair of telomere damage, respectively, causes significant growth inhibition, whereas either inhibitor alone has no effect on growth. It is reported that AKT also plays an important role in telomere stability by regulating phosphorylation and association TRF1 and TPP1 with telomeres in variety of other cancer cells (e.g., lung, fibrosarcoma, and glioblastoma), which do not require AR for either proliferation or survival. However, in CRPC cells like AR, AKT is also essential for proliferation and survival. Furthermore, it is reported that AR and PI3K/AKT pathways co-regulate one another, such that inhibition of one activates the other, thereby limiting the effectiveness of each approach. Together, these reports raise the possibility that AR inhibition in Ari-treated CRPC cells may lead to AKT activation and that thus-activated AKT may counter or limit the efficacy of ARi to induce telomere DNA damage and, thereby, limit the sensitivity of CRPC cells to ATMi. Therefore, we hypothesize that inhibition of both AR and AKT is required for maximum telomere DNA damage and activation of DDR so that CRPC cells can be hypersensitive to ATMi. Thus, treatment with AR and AKT inhibitors in combination with ATM inhibitor may offer an effective strategy for deeper and/or more durable remission of metastatic CRPC. In Aim 1, we will evaluate the effect of AKTi on telomeres in CRPC cells. Our preliminary data showed that AKTi MK2206 induces telomere DNA damage, suggesting AKT plays a role in telomere stability in CRPC cells. Extending these observations, we will determine the effect of AKTi on the association of shelterin proteins with telomeres (Aim 1a), and on telomere-associated AR (Aim 1b) in CRPC cells. We will evaluate the effect of ARi on AKT activation in CRPC cells (Aim 1c) and, finally, identify optimal conditions to disrupt telomeres and inhibit telomere repair in order to achieve maximal cell death of CRPC cells (Aim 1d). In Aim 2, we will target prostate-specific membrane antigene (PSMA) to inhibit AKT preferentially in CRPC cells. PSMA expression is increased dramatically in CRPC and its expression correlates with AKT activation. Therefore, PSMA is likely to be an attractive target to suppress AKT activity and induces telomere DNA damage, preferentially in CRPC cells, but not in healthy normal cells. Consistent with this possibility, PSMA inhibitor (PSMAi) suppressed AKT phosphorylation and induced telomere DNA damage in LNCaP cells. We
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210400
Entities
People
- Sahn-ho Kim
Organizations
- Henry Ford Health
- United States Army