By ecancer reporter Janet Fricker

Suppressing cancer cells' ability to cope with damage to their DNA could enhance the effectiveness of chemotherapy drugs, and help prevent the emergence of resistance suggest two linked studies just published in Proceedings of the National Academy of Sciences for the week of November 8.

Cancer drugs, such as cisplatin and cyclophosphamides, attack tumours by damaging DNA, thereby preventing cells from copying DNA which is necessary prior to division. Cancer cells, however, have developed the ability to use enzymes (known as translesion DNA polymerases) to copy over DNA damage allowing them to survive and spread. Indeed, enhanced DNA repair is one of the mechanisms that have been implicated in the development of resistance to conventional DNA therapy. A greater understanding of the mechanisms of resistance is therefore considered essential to improve treatment and also more broadly inform strategies to target highly drug resistant malignancies.

The researchers, led by Michael Henmann and Graham Walker, from the Massachusetts Institute of Technology (Cambridge, MA, USA), set out to explore the hypothesis that enzymes that play a role in the tumour cells' response to DNA damage might therefore offer targets for new oncology drugs. The two papers separately focused on targeting two proteins, known as Rev 3 and Rev 1, which are subunits of translesion DNA polymerases. In both studies the researchers controlled Rev1 and Rev 3 with a technique known as RNA interference, which utilizes short strands of RNA to block specific genes from being expressed.

In the first paper¹, the team studied mice with lung adenocarcinomas treated with cisplatin. They found that mice with reduced Rev3 levels lived an average of 22.5 days following cisplatin treatment, versus 11 days for mice with normal levels of Rev 3.

In the second study², mice with lymphoma were treated with cyclophosphamide. At first the drug was effective in mice with both normal and reduced Rev1 levels, but after two weeks the tumours reappeared in both groups. When the relapsed tumours were transplanted into a second group of mice drug treatment was found to be more effective in mice with reduced Rev1 – at 12 days 100 % of mice with reduced Rev1 were alive versus 40% with normal levels Rev1.

These two studies, concluded the authors, provide the first example of an alteration that prevents the acquisition of drug resistance in tumours in vivo.

"A treatment strategy based on pairing a DNA damaging chemotherapeutic agent as with a drug that inhibited the TLS (translesional DNA synthesis) mutagenic pathway could be very powerful as it could significantly reduce the rate at which cells acquire chemo-resistance," wrote the authors, who are now seeking drugs that might be able to shut down the translesional DNA polymerase system more completely.

References

1. Doles J, Oliver TG, Cameron ER (2010) REV3 suppression sensitizes drug resistant lung tumors to chemotherapy PNAS

2. Xie K, Doles J, Henmann MT, Walker C (2010) Error-prone translesion synthesis mediates acquired chemoresistance PNAS