Reducing TR4 gene expression enhances the sensitivity of prostate cancer cell lines to olaparib by inhibiting the ATM/ATR pathway

Prostate cancer (PC) has risen to become the second most common neoplasm in men, trailing only lung cancer. Individuals with advanced prostate cancer, particularly those who are resistant to androgen deprivation therapy (ADT), also known as castration-resistant prostate cancer (CRPC), have very few treatment options and a poor prognosis. Notably, advances in phase III clinical trials have highlighted the pronounced efficacy of poly adenosine diphosphate-ribose (ADP-ribose) polymerase (PARP) inhibitors in CRPC patients harbouring homologous recombination repair (HRR)-related genetic aberrations. However, HRR-related mutations occur in only 20–25% of CRPC patients. It is crucial to reduce resistance to PARP inhibitors and make them available to other CRPC patients. Testicular nuclear receptor 4 (TR4), an important molecular player involved in tumorigenesis, metastasis and chemoresistance, has emerged as a focus of investigation. Our study indicated that in prostate cancer cell lines treated with olaparib treatment, TR4 expression increased as olaparib concentrations increased. Targeting TR4 expression can alter the in vitro sensitivity of prostate cancer cell lines to olaparib. Further investigation of the molecular mechanisms revealed that down-regulating TR4 gene expression can enhance the in vitro sensitivity of prostate cancer cell lines to olaparib, which is mediated by the inhibition of the Ataxia Telangiectasia Mutated (ATM)/Ataxia Telangiectasia and Rad3-related (ATR) pathway. This study provides a novel sensitization therapeutic strategy for CRPC patients who are resistant to PARP inhibitors.

ATM/ATR pathway; CRPC; DNA damage response; NR2C2; Olaparib; PARP inhibitor; TR4

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