Exposure to endogenous (within the cell) and exogenous (outside the cell) damaging agents leads to DNA damage. Endogenous sources include oxidation, alkylation, and hydrolysis. Exogenous sources include ionizing radiation, UV radiation and chemical agents like cisplatin and etoposide. DNA damage is manifested in the form of base lesions, intra- and inter-strand cross-links, and single and double-strand breaks. Deficiency or impairment in repair can result in genomic instability or cell death. Fortunately, damage checkpoints and repair pathways exist to maintain genome integrity. Checkpoints are initiated during different cell cycle phases and recruitment of proteins like PARP, MRE11, RAD50 and NBS1 to the damage site occurs. The repair pathway chosen is dependent on multiple factors including nature of damage, cell cycle phase and chromatin environment. Mis-match, base excision, nucleotide excision, homologous recombination, non-homologous end joining, and direct reversal are some of the more prominent repair pathways.
DNA damage on its own is a well-known concept in cancer therapeutics. Chemotherapy (drugs including cisplatin, etoposide, and bleomycin) and radiotherapy work by inducing DNA damage. Despite having a weaker damage response, cancer cells resist these forms of therapy via DNA repair. Thus, a relatively new approach in cancer therapy is inhibition of repair in combination with traditional anti-cancer agents. O-6-Methylguanine- DNA-Methyltransferase has a role in removing DNA alkyl adducts and its inactivation in cancer cells in combination with alkylating agents has been shown to increase therapeutic efficacy in vivo. Mismatch repair proteins have been shown to serve as biomarkers for response to immune checkpoint inhibitors in cancer. PARP inhibitors for BRCA1/2 cancers are among the first clinically approved DNA damage targeting drugs. However, drug resistance was observed in later stages of treatment. Although damage checkpoint inactivation, repair inhibition and their combination with chemo- and radiotherapy offer great potential as cancer therapies, there are some limitations. The most obvious limitation is cancer cell selectivity. Developing inhibitors to critical repair proteins with multiple functions can turn out to be extremely dangerous for normal cells. Despite being a better weapon for killing cancer cells, combination therapy can have a worse effect in normal cells resulting in secondary mutations and tumors! A way to combat this issue can be via design of more specific inhibitors that target repair proteins with little to no functions outside of the damage response in question. Just like with any anti-cancer drug, identifying a ‘sweet spot’ for the repair inhibitor dosage wherein negative effects on normal cells are minimal can be useful. Another interesting approach is to target mitochondrial repair pathways as opposed to nuclear by exploiting the difference in mitochondrial DNA in cancer cells and normal cells.
In summary, components of DNA damage response pathways used in mono-therapy or combinational therapy are a great source for cancer therapeutics, provided an acceptable measure of specificity and selectivity is established to draw a balance between the pros and cons.
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