Tumour cells use a genetic trick to become drug-resistant

These laws, worked out in the 19th century by Gregor Mendel, an Augustinian friar, describe how heritable traits pass down through the generations, setting limits on the ways in which children can differ from their parents. Mendel’s initial experiments were on peas in the monastery garden, but his laws have since been found to apply to everything from human height to disease resistance in individual cells.

As Paul Mischel of Stanford University describes in a paper in this week’s Cell, some cancer cells refuse to play along. His work reveals that in about 20% of human cancer samples some DNA escapes from the chromosomes to which it is normally bound and forms tiny, circular bodies of extra-chromosomal DNA (ecDNA) that get scattered throughout the nucleus of a cell. Thus scattered, they are no longer subject to the rigours of mitosis, the conventional process by which chromosomes divide into two identical copies, one for each daughter cell. This adds an element of unpredictability to how genes are inherited, allowing mutations to occur faster and on a more dramatic scale.

Such cellular skulduggery had previously been seen in bacteria and fungi, which use these tricks to develop resistance to drugs. It was not until Dr Mischel began looking into the subject in 2012, however, that cancer cells were found to be equally sneaky. Since then, he and his colleagues have found that ecDNA fragments overwhelmingly contain information on defence mechanisms that the cancer cell can use to rapidly replicate and to avoid being destroyed. This may be because cells carrying such ecDNA proliferate more easily. It certainly increases the chances of harmful new traits emerging faster than would be permitted by Mendel’s rules.

It also reveals a potential vulnerability. Dr Mischel worked in close collaboration with Howard Chang, chief scientific officer at AMGEN, a biotech company, to reveal that daughter cells can benefit from ecDNA only if these circular snippets are able to weave themselves back into their chromosomes after mitosis. The ecDNA does this with the help of constituent “anchor proteins” that return it to the chromosomes and specific DNA sequences that allow it to integrate back into them.

Dr Mischel views these sequences and the anchor proteins as prime targets for future treatment. “Introducing drugs that disable or destroy them ought to leave the ecDNA adrift and remove the advantages it brings to tumour cells,” he says. That work is in its infancy, although Dr Mischel says some suitable anchor proteins have already been identified. Clinical trials are pending.

As important as ecDNA may be as a mechanism for explaining the behaviour of some aggressive cancers, “It would be an oversimplification to say that it is the only factor,” says Lillian Siu, president of the American Association for Cancer Research and oncologist at the Princess Margaret Cancer Centre in Toronto. In her view, humdrum mutations caused by genome instability and defective DNA-repair jobs contribute to the appearance of ecDNA which, in turn, may enhance such instability. Even if disabling anchor proteins can slow the rapid evolution driven by ecDNA, the forces that cause it to appear in the first place are likely to persist.