Many chemotherapy drugs, including cisplatin, cause damage to DNA and kill cancer cells by interfering with DNA replication and cell division. The damage activates cellular DNA repair mechanisms but, if the damage is too extensive, the cell undergoes apoptosis. Unfortunately, although the initial response to cisplatin is generally good, the majority of tumours will eventually develop resistance to the drug. Resistance can develop when the cell is able to replicate DNA through damaged regions using a translesion synthesis (TSL) DNA polymerase. This type of DNA replication is highly error-prone, introducing mutations into the DNA which can drive drug resistance. Suppressing the ability of tumour cells to replicate damaged DNA using the translesion synthesis DNA polymerase, Polζ has been shown to block resistance to cisplatin in human cancer cells grown in culture and now, in two papers published in PNAS, researchers at the Massachusetts Institute of Technology have shown that the approach also works in mice.
The first paper describes a tumour transplantation approach to examine the effect of impaired translesion DNA synthesis on cisplatin response in aggressive late-stage lung cancers. The researchers used RNA interference to reduce levels of Rev3, an essential component of Polζ, and showed that a 60-70% reduction doubled survival time in cisplatin-treated animals. The team also showed that Rev3-deficient cells showed reduced cisplatin-induced mutations which have been suggested to contribute to secondary malignancies following chemotherapy.
In the second study, the researchers used a mouse model of B-cell lymphoma to show that suppressing Rev1, an essential TSL scaffold protein and dCMP transferase, inhibits both cisplatin- and cyclophosphamide-induced mutagenesis. By performing repeated cycles of tumor engraftment and treatment, the team were also able to show that Rev1 plays a critical role in the development of acquired cyclophosphamide resistance.
The studies show that chemotherapy can not only select for drug-resistant populations of tumour cells but can also directly promote the acquisition of resistance-causing mutations, suggesting that blocking translesion DNA polymerases may have dual anticancer effects by both increasing the sensitivity of tumours to chemotherapy as well as reducing the potential for emergence of drug resistance during treatment. The next challenge will be to identify inhibitors of the translesion DNA polymerases.