Pollack, A. et al. The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group Trial 92–02. Clin. Cancer Res. 15, 5478–5484 (2009).

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Protein kinase A (PKA), a member of the cyclic AMP-dependent holoenzyme family, is associated with cell proliferation and tumorigenesis. Specifically, PKA is involved in cell-cycle progression from the G1 phase to the S phase, and its overexpression can overcome growth factor requirements for cell proliferation. Knockdown of the PKA type Iα regulatory subunit (PKARIα) in prostate cancer cells results in significant inhibition of tumor cell proliferation both in vitro and in vivo when combined with radiation and androgen-deprivation therapy. Likewise, inhibition of PKA expression by antisense oligonucleotides in colorectal, breast and gastric carcinoma cell lines results in reduced cell growth and improved response of colorectal and ovarian cancer cell lines to radiotherapy and chemotherapy. Moreover, results from the Radiation Therapy Oncology Group (RTOG) trial 86–10 demonstrated that PKARIα expression levels in prostate cancer were predictive of outcome, as they correlated significantly with the rate of distant metastases in patients treated with radiotherapy alone or radiotherapy with short-term androgen deprivation therapy. PKA overexpression in colorectal, breast and lung cancers has been linked with poor outcome in patients. PKA, therefore, might be a potential therapeutic target and might enhance the response to therapy in patients with high-risk prostate cancer treated with radiation and androgen deprivation.

...PKARIα expression levels and the duration of androgen deprivation therapy were associated with patients' outcomes

Pollack and colleagues conducted analyses in an independent cohort of patients with prostate cancer who were treated with radiation and either short-term (4 months) or long-term (28 months) androgen deprivation therapy as part of the RTOG 92–02 trial. These subgroup analyses aimed to confirm the potential role of PKA in patients with high-risk prostate cancer. Patients started receiving androgen deprivation 2 months before radiotherapy was initiated. The researchers examined tissues from pretreatment diagnostic biopsies from 313 patients with high-risk prostate cancer who were treated with radiation and androgen deprivation therapy and were followed up for a median of 10.1 years. PKARIα expression was analyzed by immunohistochemistry and quantified both manually and by image analysis. The researchers used multivariate analyses to assess the relationship between PKARIα expression levels and patients' outcomes.

Pollack and colleagues found a strong correlation between manual and image analysis measurements of PKARIα expression levels. Moreover, these levels were in agreement with the results from the RTOG 86–10 study, both in terms of manual and image analysis quantification and patients' outcomes (namely, biochemical failure, local failure, cause-specific mortality and overall mortality). Analyses were adjusted for age, initial prostate-specific antigen value, Gleason score, clinical T stage and treatment. PKARIα expression levels were a significant predictor of outcome in patients with prostate cancer who were treated with radiation and androgen deprivation therapy in the primary setting. Overexpression of PKARIα in tumor tissues was related to biochemical and local failure and to distant metastases.

Furthermore, PKARIα expression levels and the duration of androgen deprivation therapy were associated with patients' outcomes. Pollack and colleagues suggest that levels of this marker are a significant predictor of outcome in patients with prostate cancer, and comment that “overexpression may reduce the gains expected from long-term androgen deprivation plus radiation therapy relative to short-term androgen deprivation plus radiation therapy”. Patients with tumors that expressed high levels of PKARIα had a diminished response to long-term androgen deprivation and radiation therapy compared with those whose tumors expressed low levels of PKARIα. As high PKARIα expression levels in tumors were associated with diminished benefit from long-term androgen deprivation therapy, strategies such as PKARIα knockdown might provide a benefit for these patients.

“The results from this investigation provide further evidence that PKARIα has a central role in mediating response to androgen deprivation and support the rationale for PKARIα knockdown in men [whose tumors demonstrate] PKARIα overexpression”, conclude the researchers.