Abstract 3577: The role of Checkpoint Kinase 2 in the regulation of androgen receptor signaling and prostate cancer cell growth during progression to castration resistance.
Authors: Ta Huy Q. , Ivey Melissa L. , Gioeli Daniel 
Published: August 2014

As the second leading cause of cancer deaths in men, prostate cancer is a persistent, significant challenge for clinicians and researchers. Almost all patients with disseminated prostate cancer initially respond to androgen deprivation therapy. However, virtually every patient will relapse due to the growth of castration-resistant cancer cells and develop metastatic and lethal disease. Even with the recent development of new androgen ablation treatments such as Abiraterone and Enzalutamide, castration-resistant prostate cancer is still incurable. We hypothesize that compensatory signaling mechanisms that limit the effectiveness of androgen ablation can be overcome with therapeutic strategies targeting kinase cascades. In order to identify signaling pathways that regulate AR activity and prostate cancer cell growth we screened a panel of shRNAs targeting the human kinome in LNCaP prostate cancer cells grown in the presence and absence of androgen. We discovered that knockdown of Checkpoint Kinase 2 (CHK2) dramatically increased LNCaP prostate cancer cell proliferation. This observation is clinically relevant since CHK2 inactivating mutations arise in over 10% of prostate cancer patients and CHK2 expression decreases as prostate cancer progresses to a castration-resistant disease. Consistent with these clinical observations, CHK2 knockdown did not affect cell growth in the castration resistant C4-2 cell line, suggesting that the selection of the castration resistant C4-2 line from LNCaP involved the same effector as observed in clinical specimens. Consistent with this, CHK2 expression is lower in C4-2 cells compared to LNCaP. We determined that CHK2 knockdown increases androgen receptor (AR) transcriptional activity on both androgen activated and androgen repressed genes, providing evidence that CHK2 affects prostate cancer cell proliferation, at least in part, through the AR. These data suggest that CHK2 is a negative regulator of androgen sensitivity and prostate cancer cell growth and that CHK2 is lost during the progression to castration resistance. We are examining the role of CHK2 in regulating androgen-AR signaling, growth, and survival of prostate cancer cells; specifically we are identifying the crucial intracellular proteins that mediate CHK2 signaling and growth regulation of prostate cancer cells. Since CHK2 signaling is activated by DNA damage, such as that triggered by radiation therapy and brachytherapy, understanding how CHK2 signaling regulates the AR will provide critical insights into how we can combine current therapies with androgen blockade for greater clinical effectiveness.

Citation Format: Huy Q. Ta, Melissa L. Ivey, Daniel Gioeli. The role of Checkpoint Kinase 2 in the regulation of androgen receptor signaling and prostate cancer cell growth during progression to castration resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3577. doi:10.1158/1538-7445.AM2013-3577