Linking hormonal and radiation therapies for prostate cancer - a review

Surgery, radiation and androgen deprivation are three important therapeutic modalities for prostate cancer. Initial responses are common but almost all patients will relapse and progress to develop castration-resistant prostate cancer.

Previous studies suggest that checkpoint kinase 2 (CHK2) gene plays a role in protecting cancer cells from the effects of radiation therapy. A recent study by Ta. et al. published in the journal Cancer Research identified a novel link between sensitivity to radiation therapy and hormonal therapy mediated through CHK2. The investigators initially started with a high-throughput RNA interference screen knocking down individual genes to identify relevant signaling pathways regulating prostate cancer cell growth. This screen showed that knockdown of CHK2 dramatically increased prostate cancer growth and increased their sensitivity to androgen deprivation. The study also found evidence of a feedback loop between androgen receptor (AR) and CHK2. The authors also conducted immunohistochemical analysis of prostate cancer patient samples showed a loss of CHK2 as tumors progressed to castration-resistant prostate cancer. This interesting study provides novel insights into the role of CHK2 as a tumor-suppressor, the loss of which is important for transition into the castrate-resistant state. The study also supports a rational and mechanistic basis for possible new therapeutic approaches for sensitizing CRPC to both androgen deprivation therapy and radiation.

Written by: Bishoy Faltas MD  

References: Ta HQ, Ivey ML, Frierson HF Jr, Conaway MR, Dziegielewski J, Larner JM, Gioeli D. Checkpoint Kinase 2 Negatively Regulates Androgen Sensitivity and Prostate Cancer Cell Growth. Cancer Res. 2015 Dec 1; 75(23):5093-105. doi: 10.1158/0008-5472.CAN-15-0224.

Prostate cancer is the second leading cause of cancer death in American men, and curing metastatic disease remains a significant challenge. Nearly all patients with disseminated prostate cancer initially respond to androgen deprivation therapy (ADT), but virtually all patients will relapse and develop incurable castration-resistant prostate cancer (CRPC).
A high-throughput RNAi screen to identify signaling pathways regulating prostate cancer cell growth led to our discovery that checkpoint kinase 2 (CHK2) knockdown dramatically increased prostate cancer growth and hypersensitized cells to low androgen levels. Mechanistic investigations revealed that the effects of CHK2 were dependent on the downstream signaling proteins CDC25C and CDK1. Moreover, CHK2 depletion increased androgen receptor (AR) transcriptional activity on androgen-regulated genes, substantiating the finding that CHK2 affects prostate cancer proliferation, partly, through the AR. Remarkably, we further show that CHK2 is a novel AR-repressed gene, suggestive of a negative feedback loop between CHK2 and AR. In addition, we provide evidence that CHK2 physically associates with the AR and that cell-cycle inhibition increased this association. Finally, IHC analysis of CHK2 in prostate cancer patient samples demonstrated a decrease in CHK2 expression in high-grade tumors. In conclusion, we propose that CHK2 is a negative regulator of androgen sensitivity and prostate cancer growth, and that CHK2 signaling is lost during prostate cancer progression to castration resistance. Thus, perturbing CHK2 signaling may offer a new therapeutic approach for sensitizing CRPC to ADT and radiation. Cancer Res; 75(23); 1-13. ©2015 AACR.

Cancer research. 2015 Nov 16 [Epub ahead of print]


Huy Q Ta, Melissa L Ivey, Henry F Frierson, Mark R Conaway, Jaroslaw Dziegielewski, James M Larner, Daniel Gioeli
Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. , Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. , Department of Pathology, University of Virginia Health System, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. , Cancer Center Member, University of Virginia, Charlottesville, Virginia. Department of Radiation Oncology, University of Virginia, Charlottesville, Virginia. , Departments of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. Cancer Center Member, University of Virginia, Charlottesville, Virginia.

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