Targeted inhibition of the CREB1-CtIP axis enhances the efficacy of abiraterone combined with radiotherapy in prostate cancer.

In the treatment of locally advanced prostate cancer (PCa), abiraterone acetate (AA) serves both as a commonly used therapeutic agent and a radiosensitizer when combined with radiation therapy (RT). However, this combination therapy is not effective for all patients, and prolonged treatment may lead to decreased therapeutic sensitivity. Our study found that the combination of abiraterone (Abi, the active component of abiraterone acetate in vivo) and RT increases the expression of CtBP-interacting protein (CtIP) in prostate cancer cells, and elevated CtIP levels in PCa are associated with poor prognosis. CtIP has been demonstrated to be a key protein in the homologous recombination repair (HR) pathway of DNA damage repair (DDR). Furthermore, we observed that both Abi and RT enhance the transcriptional activity of CREB1 via phosphorylation, thereby modulating CtIP expression. Additionally, during the transition from normal prostate cells to prostate cancer cells, DNA demethylases (TETs) reduce DNA methylation levels in the promoter region of CtIP, facilitating the binding of CREB1 to the CtIP promoter. Finally, our in vitro and in vivo experiments indicate that the CREB1 phosphorylation inhibitor 666-15 significantly enhances the therapeutic efficacy of Abi-RT combination therapy. In summary, our study reveals that inhibition of the CREB1-CtIP axis effectively improves the therapeutic outcomes of Abi-RT combination therapy, which may offer a novel clinical strategy for the treatment of prostate cancer.