Targeting the Plk1/Pdcd4/mTORC2 Signaling to Treat Castration-Resistant Prostate Cancer

点击翻译按钮获取中文摘要

Title: Targeting the Plk1/Pdcd4/mTORC2 signaling to treat castration-resistant prostate cancer Abstract Androgen receptor (AR) signaling is essential for development of prostate cancer (PCa), including castration- resistant prostate cancer (CRPC). Consequently, androgen signaling inhibitors (ASIs), such as abiraterone and enzalutamide, are becoming the first line treatment for CRPC. However, the limited success of ASIs makes it urgent to develop approaches to treat CRPC patients who are no longer responsive to ASIs. Programmed cell death 4 (Pdcd4) is a tumor suppressor, which has been demonstrated to inhibit tumor progression and chemoresistance. Furthermore, Pdcd4 is an androgen-repressed protein that regulates PCa growth and castration resistance. As such, it will be of clinical significance to understand the regulation mechanism of Pdcd4, as it will reveal novel approaches to overcome ASI resistance. Polo-like kinase 1 (Plk1), a critical regulator of cell cycle-related events, is a documented target for PCa treatment. Of note, we previously demonstrated that inhibition of Plk1 enhances the efficacy of ASIs. The long-term goals of this study are to identify druggable signaling pathways that offer effective treatment options for patients with CPRC who are no longer responsive to ASIs. The objective is to define the role of Plk1 in regulating Pdcd4 and to exploit these pathways as a novel therapeutic target for CRPC. Our data show that 1) Pdcd4 enhances the sensitivity to enzalutamide due to inhibition of mTORC2 (the mammalian target of rapamycin complex 2) and AR expression; 2) Plk1 phosphorylation of Pdcd4 results in its protein degradation; and 3) the dominant negative Pdcd4 peptide (TAT- RBD) overcomes ASI resistance in PCa. Based on these observations, we aim to test the central hypothesis that Plk1-associated phosphorylation of Pdcd4 results its degradation, which causes subsequent activation of the mTORC2, eventually contributing to activation of AR signaling and ASI resistance. Our hypothesis will be tested by pursuing three Specific Aims - (1) to demonstrate that loss of Pdcd4 to activate mTORC2 contributes to ASI resistance; (2) to dissect how Plk1 phosphorylation of Pdcd4 regulates its function as a tumor suppressor; and (3) to analyze clinical significance of Plk1 phosphorylation of Pdcd4. These complementary aims will be accomplished using biochemical analyses of signaling intermediates and employing genetic strategies with culture systems, inducible PCa mouse models, patient-derived xenograft (PDX) and human PCa samples. The rationale for the research is that it will probe the importance of Plk1-associated activity to Pdcd4 and to examine whether TAT-RBD peptide is a novel approach to treat ASI-resistant CRPC. This contribution is significant because, if positive, the results of the proposed study will support an immediate clinical trial for TAT-RBD peptide to treat CRPC that not respond to ASIs. The multiple-PI team, consisted of complementary expertise on Plk1 (X. Liu) and Pdcd4 (Yang), as well as prostate cancer pathology (Allison) and biostatistics (Chen), will be able to finish the proposed research in a timely manner.