Targeting DNA Repair in Anti-Cancer Treatments
Treatment of cancer started long before the emergence of modern pharmaceuticals, and over the decades, mankind has tried just about everything to battle this disease. Besides surgery, only a handful of treatments have stood the test of time: ionizing radiation, discovered by Wilhelm Röntgen, and chemotherapy treatments, discovered serendipitously in the release of mustard gas following the bombing of an American cargo ship in Bari (Italy) during the Second World War. Antimetabolites and natural products were also found to have potent anti-cancer effects and much later it was discovered that all the anti-cancer drugs share the same target: DNA. Hence, there is overwhelming evidence that causing DNA damage is an effective way of treating cancer.
DNA was for a long time thought to be highly stable, a prevailing view until Tomas Lindahl discovered the spontaneous decay of DNA (Lindahl and Andersson 1972; Lindahl and Nyberg 1974). As DNA is indispensable for life, Dr. Lindahl hypothesized that there must be a way to repair the DNA and subsequently he identified the first DNA repair protein, a uracil DNA glycosylase (Lindahl 1974). For this discovery he got the 2015 Nobel Prize in Chemistry, which he shared with Drs. Paul Modrich and Aziz Sancar for their discoveries of other DNA repair pathways. Over the years, hundreds of DNA repair proteins have been identified and their individual role has been studied in great biochemical detail (Hoeijmakers 2001).
Although DNA damaging agents dramatically improved cancer survival rates and prolonged life, it was evident early on that cancers relapsed and developed resistance. For clinicians it was clear that the cancer cells somehow escaped the treatments and a likely mechanism was by improving their ability to repair DNA. Hence, a way to decrease the DNA repair capacity of cancer cells has been on the agenda for a long time to improve cancer treatment, in particular in the radiation oncology field. The big issue has always been how to selectively sensitize the cancer cells and not the non-transformed cells?
KeywordsDNA repair DNA damage response Synthetic lethality Replication stress
I thank Sean Rudd for helpful input. The laboratory is mainly funded by Knut and Alice Wallenberg Foundation, the Swedish Research Council, the European Research Council, Swedish Cancer Society, the Swedish Children’s Cancer Foundation, the Strategic Research Foundation, the Swedish Pain Relief Foundation, AFA foundation, and the Torsten and Ragnar Söderberg Foundation.
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