PRKDC and cancer: Targeting DNA-PKcs by siRNA or pharmacological inhibition leads to potentiation of cancer cells to radiation and chemotherapy.225,226 This finding evoked a great deal of interest in DNA-PKcs inhibitor development, some of which have advanced into clinical investigation.227 Unfortunately, most DNA-PKcs inhibitors have been deprioritized from clinical development, including DNA-PKcs selective inhibitors M3814228 and AZD7648.229 Both M3814 and AZD7648 are ATP-competitive inhibitors, and demonstrated selectivity over other PIKK kinases.