Chao CS, et al. - This study’s findings demonstrate the role of DNA damage response (DDR) genes, especially, DNA-PKc in promoting resistance to taxanes in metastatic castrate-resistant prostate cancer (mCRPC). It has been considered that targeting prostatic DNA-PKc may provide a novel strategy to restore taxane sensitivity in taxane-refractory mCRPC.

• As per the findings, DDR pathway-specific gene profiling showed significant upregulation of PRKDC and CDK7, and downregulation of MSH3 in DU145-DxR cells.

• DU145-DxR cells sustained significantly less DNA damage when exposed to etoposide and docetaxel in comparison with parental DU145.

• The findings indicate that pharmacologic inhibition of DNA-PKc, a component of NHEJ repair machinery, with all three inhibitors, significantly resensitized DU145-DxR cells to docetaxel.

• Moreover, DNA-PKc inhibition also resensitized DU145-DxR to cabazitaxel and etoposide, which indicated cross-resistance.

• The finding suggested that inhibition of DNA-PKc led to elevated DNA damage in etoposide- and docetaxel-treated DU145-DxR cells.

• Moreover, DNA-PKc inhibition did not affect MDR1 activity, demonstrating that DNA-PKc inhibitors resensitized taxane-resistant cells via an MDR1-independent mechanism.