Abstract
Physical and chemical DNA-damaging agents are used widely in the treatment of cancer. Double-strand break (DSB) lesions in DNA are the most deleterious form of damage and, if left unrepaired, can effectively kill cancer cells. DNA-dependent protein kinase (DNA-PK) is a critical component of nonhomologous end joining (NHEJ), one of the two major pathways for DSB repair. Although DNA-PK has been considered an attractive target for cancer therapy, the development of pharmacologic DNA-PK inhibitors for clinical use has been lagging. Here, we report the discovery and characterization of a potent, selective, and orally bioavailable DNA-PK inhibitor, M3814 (peposertib), and provide in vivo proof of principle for DNA-PK inhibition as a novel approach to combination radiotherapy. M3814 potently inhibits DNA-PK catalytic activity and sensitizes multiple cancer cell lines to ionizing radiation (IR) and DSB-inducing agents. Inhibition of DNA-PK autophosphorylation in cancer cells or xenograft tumors led to an increased number of persistent DSBs. Oral administration of M3814 to two xenograft models of human cancer, using a clinically established 6-week fractionated radiation schedule, strongly potentiated the antitumor activity of IR and led to complete tumor regression at nontoxic doses. Our results strongly support DNA-PK inhibition as a novel approach for the combination radiotherapy of cancer. M3814 is currently under investigation in combination with radiotherapy in clinical trials.
Highlights
To ensure the accurate maintenance and transfer of genetic information to progeny, mammalian cells have evolved sophisticated mechanisms to sense DNA damage, coordinate its repair, and prevent potential tumorigenic effects; this is collectively known as the DNA damage response (DDR)
phosphoinosiditde 3-kinase (PI3K) kinases, Ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), mammalian target of rapamycin, and DNAdependent protein kinase (DNA-PK), are members of the PI3K-related kinase family, which is characterized by high similarity in the kinase domain [21]
M3814 is a potent inhibitor of DNA-PK catalytic activity with remarkable selectivity against most of the 284 protein kinases we tested, including the closest members of its own kinase family
Summary
To ensure the accurate maintenance and transfer of genetic information to progeny, mammalian cells have evolved sophisticated mechanisms to sense DNA damage, coordinate its repair, and prevent potential tumorigenic effects; this is collectively known as the DNA damage response (DDR). Defects in the DDR contribute to genomic instability and represent one of the key hallmarks of cancer [1]. Many established therapeutic modalities, such as radiotheraphy and chemotherapy that attack cancer cell DNA are in clinical use but provide limited benefit to patients with cancer. This is due, at least in part, to the competence of tumor cells to deal with DNA damage [2]. Diverse types of lesions can be generated in DNA, ranging from base modifications to strand breaks, leading to large deletions or genomic rearrangements.
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