Abstract
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.
Highlights
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs)
Studies showing that loss of ataxia-telangiectasia mutated (ATM) kinase, a cardinal kinase in DDR, or deficiency in MutS homologue 3 (MSH3) increases cellular sensitivity to DNA-PK inhibitor (KU0060648) treatment[25,26,27] suggest that there may be opportunities for combination with other inhibitors of DDR, if those effects are significantly enhanced by tumour-specific DDR deficiencies such as in ATM signalling
While tumours were insensitive to single-agent AZD7648 treatment, ionizing radiation (IR) treatment alone induced tumour growth inhibition (TGI) by 50%, but the combination of AZD7648 with IR (AZD7648 followed by IR 1 h later in the first 5 days of the study) achieved 90% TGI
Summary
DNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies Tumour cells manage their inherent genomic instability through the detection and repair of DNA lesions by a process termed the DNA damage response (DDR), which triggers intracellular signalling events, regulates processes including cell cycle progression and promotes DNA repair. The importance of DNA-PK activity in repairing pathological DNA DSBs is illustrated by studies showing that DNA-PKcs genetic deficiencies sensitize cells to IR and other DSB-inducing agents[16,17,18] This highlights the suitability of using a DNA-PK inhibitor as a combination partner with IR and topoisomerase II inhibitors such as doxorubicin and etoposide. Studies showing that loss of ataxia-telangiectasia mutated (ATM) kinase, a cardinal kinase in DDR, or deficiency in MutS homologue 3 (MSH3) increases cellular sensitivity to DNA-PK inhibitor (KU0060648) treatment[25,26,27] suggest that there may be opportunities for combination with other inhibitors of DDR, if those effects are significantly enhanced by tumour-specific DDR deficiencies such as in ATM signalling
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