Chemical inhibition of DNA repair kinases as a promising tool in oncology

Abstract

Background. DNA repair pathways play a major role in tumour resistance towards chemo-and radiotherapy. Therefore, inhibitors of specific DNA repair pathways might be advantageous when used in combination with DNA-damaging agents, such as ionizing radiation. This review put particular emphasis on the key DNA repair enzymes: DNA-dependent protein kinase (DNA-PK), ataxia-telangiectasia mutated kinase (ATM) and ATM-Rad3-related kinase (ATR) and their specific inhibitors in the context of radio-sensitization. Results. We reviewed recent studies on novel and potent inhibitors and found evidence that inhibitors of DNA repair pathways such as small molecule inhibitors could be efficient and selective in tumour cells. Interpretation of recent literature results accompanied with implications for practice and further research are presented. Conclusions. The prospects of targeting DNA repair enzymes to treat cancer are optimistic, but future work will show if this approach has a significant in vivo efficacy, since we are still waiting for the inhibitor which would pass all phases in clinical trials. In spite of the fact that a number of drugs possess interesting synergy of radiotherapy in vitro, the future use will depend on developing compounds with improved solubility and the serum half-life. Normal tissue toxicity leading to a significant increase of radiotherapy efficiency remains a key question that might be answered only by clinical trials.

Radioresistance of chordoma cells is associated with the ATM/ATR pathway, in which RAD51 serves as an important downstream effector

“…The expression levels of signaling molecules were mapped relative to the ATM/ATR pathway in chordoma tissues and adjacent normal tissues. ATM and ATR are apical DNA damage signaling kinases that phosphorylate substantial downstream molecules ( 4 , 5 ). IHC detection revealed that p-ATM staining was present in the nucleus and cytoplasm of adjacent normal cells of chordomas in all patients; however, staining was markedly more abundant in the cancer cells ( Fig.…”

“…It has been reported that irradiation induces DNA repair mechanisms, which serve as a protective action against apoptosis triggered by radiation-induced DNA damage ( 8 ). ATM/ATR are central modulators of DNA repair mechanisms in diverse cancer types upon ionizing radiation ( 4 – 6 ); however, little evidence is available to clarify the role of the ATM/ATR pathway in chordomas. The present study initially investigated the abundance and location of signal molecules related to the ATM/ATR pathway in chordomas and adjacent non-cancer tissues to elucidate the basic expression profile.…”

“…Several lines of evidence have demonstrated that DNA repair mechanisms are employed by cancer cells to resist ionizing radiation, resulting in cancer recurrence and final radiotherapy failure ( 4 – 6 ). It has been reported that the protein kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3 related (ATR), are major regulators in the DNA damage response to radiation ( 4 , 5 ). An increased number of ATM and ATR foci have been observed in damaged DNA following γ-ray and carbon ion irradiation ( 6 ).…”

Involvement of classic and alternative non-homologous end joining pathways in hematologic malignancies: targeting strategies for treatment

“…Another novel strategy is to use Dbait (DNA strand break bait) molecules, which mimic DSBs and trap DNA-PK and PARP. Thereby, by generating a false DNA damage signal, they inhibit the recruitment of key repair proteins [193,194] NU7026 Primary CLL cells Synergistic effects with chlorambucil [195] CC-115 CLL, NHL, and MM Phase I clinical trial A dual inhibitor of DNA-PK and mTOR [177,196] IC86621 NHL and HL Synergistic effects with bleomycin and etoposide [183] CC-122 (Avadomide) NHL and MM Phase I clinical trial [178,197] NU7441 Pre-B ALL cells Increase of chemosensitivity to doxorubicin [198] OK-1035 L5178Y cells (lymphoma cell line) Preclinical testing [199] Dbait (AsiDNA or DT01) Lymphoma and leukemia cells 32 bp double-stranded DNA fragment that mimics DNA lesion and traps DNA repair enzymes A dual inhibitor of DNA-PK and PARP1 [191] GRN163L (Imetelstat) CLL Imetelstat sensitizes primary CLL lymphocytes to fludarabine A dual inhibitor of DNA-PK and telomerase [192] at the damage site and ultimately prevent the repair of DNA damage. AsiDNA, a cholesterol form of Dbait, exerts synergistic effects in combination with etoposide, cyclophosphamide, and radiotherapy against lymphoma and leukemia cell lines without increasing their toxicity to normal blood cells [191].…”

Protein Tyrosine Kinase-6 (PTK6)

“…Alterations in DNA-PK expression or activity suggest that the consequences of its inhibition should be useful in antitumor therapy. Therefore, DNA-PK became an attractive target in oncology and a variety of different strategies has been applied in cancer treatment (Durisova et al 2016).…”