DNA-PKcs Is a Therapeutic Target in ATM-Deficient Tumors

Inactivation of the ataxia telangiectasia mutated (ATM) kinase impairs homologous recombination (HR)–mediated repair of DNA double-strand breaks (DSB). In addition, recent studies have shown that loss of ATM protects cancer cells from p53-driven apoptosis and confers resistance to genotoxic chemotherapeutic agents such as etoposide, suggesting that these cells may utilize the alternative repair pathway of nonhomologous end joining (NHEJ) for DNA repair and cell survival. Consistent with this idea, Riabinska and colleagues found that inhibition or knockdown of protein kinase, DNA-activated, catalytic polypeptide (PRKDC, also known as DNA-PKcs), which is required for NHEJ, potently induced apoptosis in ATM-defective but not ATM-proficient human and murine cancer cell lines and primary chronic lymphocytic leukemia cells. The sensitivity of ATM-deficient cells to DNA-PKcs inhibition was not accompanied by increased expression of DNA-PKcs, suggestive of nononcogene addiction. Mechanistically, pharmacologic blockade of DNA-PKcs prevented efficient DNA repair in ATM-defective cells following etoposide treatment, resulting in the persistence of DSBs and subsequent accumulation of CtBP-interacting protein–generated single-stranded DNA (ssDNA) coated with replication protein A (RPA). These RPA-bound ssDNA repair intermediates stimulated apoptosis in ATM-defective cells treated with DNA-PKcs inhibitor via activation of the ataxia telangiectasia and RAD3-related (ATR)–CHK1–p53 pathway and induction of the proapoptotic gene p53 upregulated modulator of apoptosis (PUMA), as CHK1 inhibition or depletion of PUMA suppressed DNA-PKcs inhibitor-induced apoptosis. Importantly, treatment with DNA-PKcs inhibitor alone or in combination with etoposide decreased the growth of ATM-deficient murine lymphoma cells in vivo and prolonged the survival of tumor-bearing mice. Although additional studies are necessary to validate these results in human tumors, these findings establish a synthetic lethal interaction between ATM and DNA-PKcs and suggest that DNA-PKcs inhibitors may provide therapeutic benefit to patients with chemotherapy-resistant, ATM-defective tumors.

Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, et al. Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med 2013;5:189ra78.

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