Inhibition of Serum Response Factor Improves Response to Enzalutamide in Prostate Cancer.

Abstract

Simple SummaryDespite the improvement in the treatment options for prostate cancer patients, we still lack effective treatments when the cancer has spread outside the prostate. Therefore, there is an urgent need to develop new therapies that will work better in this setting. Our study has identified one central factor, the serum response factor (SRF), which controls many genes associated with prostate cancer development. We have shown that an SRF inhibitor can stop the cancer cells from dividing and surviving. When this inhibitor is used in combination with current treatments, these are more effective in killing cancer cells. We also confirmed the relevance of SRF to patients by looking at its abundance in prostate cancer tissues from patients. We showed that patients who did not respond to current treatments had significantly higher levels of SRF. We are currently investigating SRF inhibitor mechanisms and hope that these drugs will soon be available to patients.Castrate-resistant prostate cancer (CRPC) is challenging to treat with the androgen receptor (AR), the main target and key focus of resistance. Understanding the mechanisms of AR interaction with co-regulators will identify new therapeutic targets to overcome AR resistance mechanisms. We previously identified the serum response factor (SRF) as a lead target in an in vitro model of CRPC and showed that SRF expression in tissues of CRPC patients was associated with shorter survival. Here, we tested SRF inhibition in vitro and in vivo to assess SRF as a potential target in CRPC. Inhibition of SRF with the small-molecule inhibitor CCG1423 resulted in enhanced response to enzalutamide in vitro and reduced tumour volume of LuCaP 35CR, a CRPC patient-derived xenograft model. Nuclear localisation of AR post-CCG1423 was significantly decreased and was associated with decreased α-tubulin acetylation in vitro and decreased prostate specific antigen (PSA) levels in vivo. SRF immunoreactivity was tested in metastatic tissues from CRPC patients to investigate its role in enzalutamide response. Kaplan–Meier curves showed that high SRF expression was associated with shorter response to enzalutamide. Our study supports the use of SRF inhibitors to improve response to enzalutamide.