Abstract

    Targeting of
DNA repair pathways in cancer remains an attractive concept for enhancing the
efficacy of radio- and chemotherapy. However, the key role of DNA repair in
normal tissue presents challenges for development of a strategy that provides
an effective therapeutic index. We discovered
NU5455: a novel, selective orally-bioavailable small molecule inhibitor of
DNA-dependent protein kinase (DNA-PK). DNA-PK is critical for repair of double
strand breaks (DSB) induced by ionising radiation and Topoismerase II poisons
(e.g. etoposide, doxorubicin) and thus we examined the capacity for NU5455 to
potentiate the effects of these agents in vitro and in vivo. NU5455
significantly enhanced the cytotoxicity of a large panel of human and mouse
tumour cell lines in a manner that was independent of TP53 status or growth
phase, and by a mechanism involving disruption of non-homologous end-joining
and subsequent inhibition of DNA DSB repair. In vivo, NU5455 significantly
augmented the anti-tumour effect of targeted radiotherapy in human lung tumours
without potentiating DNA-damage or toxicities in normal tissues. Since the
activity and expression of the DNA-PK catalytic subunit is associated with
chemoresistance in hepatocellular carcinoma (HCC), we also reasoned that
targeting DNA-PK would significantly sensitise HCC cells to doxorubicin-induced
DSB. We directly implanted doxorubicin-eluting beads into HCC tumours, to
mirror the clinical use of localised TACE (trans arterial chemoembolisation)
treatment. Using this model, oral administration of NU5455 in combination with
localised doxorubicin-eluting beads, produced a significantly enhanced tumour
growth delay. Collectively,
these data confirm that inhibition of DNA-PK has significant potential as a
chemo- and radio-potentiation strategy, and that the duration of DNA-PK
inhibition and localisation of DNA-damage is key to maximising the therapeutic
index of this approach.