DNAPK Inhibition Preferentially Compromises the Repair of Radiation-induced DNA Double-strand Breaks in Chronically Hypoxic Tumor Cells in Xenograft Models

Abstract

Radiation-induced DNA double strand breaks (DSBs) can be repaired by homologous recombination (HR) and non-homologous end joining (NHEJ). Recently, it has been found that chronic tumor hypoxia compromises HR repair of DNA DSBs, but activates the NHEJ protein DNAPK. We therefore hypothesized that inhibition of DNAPK can preferentially potentiate the sensitivity of chronically hypoxic cancer cells to radiation through contextual synthetic lethality in vivo. In this study, we investigated the impact of DNAPK inhibition by a novel selective DNAPK inhibitor, NU5455, on the repair of radiation-induced DNA DSBs in chronically hypoxic and nonhypoxic cells across a range of xenograft models. We found that NU5455 inhibited DSB repair following radiation in both chronically hypoxic and nonhypoxic tumor cells. Most importantly, the inhibitory effect was more pronounced in chronically hypoxic tumor cells than in nonhypoxic tumor cells. This is the first in vivo study to indicate that DNAPK inhibition may preferentially sensitizes chronically hypoxic tumor cells to radiotherapy, suggesting a broader therapeutic window for transient DNAPK inhibition combined with radiotherapy.

Exploring hypoxic biology to improve radiotherapy outcomes

“…Moreover, another study also found that DNA-PK inhibitor NU5455 may preferentially sensitise chronically hypoxic tumour cells to radiotherapy in vivo (Ref. 184). Another study showed that DNA-PKcs inhibition potentially overcome hypoxia-induced radioresistance in NSCLC by the combination of ionising radiation treatment with the DNA-PK inhibitor M3814 (Ref.…”

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…Microsatellite instability (MSI) resulting from mismatch repair deficiency exists in an SL relationship with WRN helicase, which is essential for microsatellite stable and widespread DSB 55,56 . The alteration of nucleotide excision repair (NER) genes (ERCC2/3, two subunits of the TFIIH complex) confers cancer cell powerful sensitivity to DNA strand crosslink or alkylation under the platinum or irofulven chemotherapy 57–59 . The fusion transcription factors EWS/FLI in Ewing sarcoma cells synergistically produce SL upon CDK12 inhibition, which preferentially suppresses the gene expression in DNA repair 60 .…”