There are two related and interesting articles on cancer evolution in a recent edition of eLife. The first is a commentary by Devon M Fitzgerald and Susan M Rosenberg, of the Baylor College of Medicine, on a paper in the same issue  titled “TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells.” As Fitzgerald and Rosenberg explain, mutations don’t always arise randomly at uniform rates. Many cells and organisms have been shown to increase mutagenesis in response to stress. In the case of cancer this could come about through the insult to cancer cells of anti-cancer medication. The paper by Raffaella Sordella, and her colleagues, of Cold Spring Harbor Laboratory documents a good example of this by showing that TGF-beta signaling can temporarily reduce the fidelity of DNA repair leading to genetic diversity in progeny cells. This can result in the evolution of resistance to chemotherapy.

The CSHL team concentrated on CD44+/CD24− cells which arise in cancer cell lines and behave like stem cells in reaction to the TGF-beta signaling pathway so that they become continuously active. These cells are linked to drug-resistance, metastasis and other poor outcomes for patients, they say. The faulty DNA repair causes copy number changes to genes – a well recognised hall-mark of cancer evolution. They also showed that the gene PMS1 – which is important for so-called mismatch-repair of DNA was also less active in CD44+/CD24− cells. Mismatch repair corrects small errors in DNA replication, and so errors here can allow thousands of small point mutations to pile up in cancer cells.

All this, say Fitzgerald and Rosenberg, points to the importance of looking for “anti-evolvability” drugs rather than drugs which try to deal with the outcomes of cancer evolution. By inhibiting evolution you could, theoretically, decrease the chances of the evolution of resistance.