Cassandra Willyard in Scientific American:
Cancer cells harbour a staggering array of mutations. In 2012, when Swanton and his colleagues sequenced multiple biopsies from two people with kidney cancer, they found that even within a single person, no two samples were the same. The team examined not only the primary tumour, but also the satellite tumours—called metastases—that had spread throughout the patients' bodies. In each person, the team found more than 100 mutations in the various tumour samples analysed; only about one-third of them occurred in all samples. The relationships between the various cancerous cells from a single person can be plotted out in much the same way as evolutionary biologists plot relationships between species: by drawing phylogenetic trees, branching diagrams that trace 'descendants' back to a common ancestor. Mutations that occur in the first malignant cells, those in the trunk of this evolutionary tree, will end up in all the tumour cells; mutations that arise later will be found only in the tree's branches. To eliminate the tumour, Swanton says, one must attack the mutations in the trunk.
Therapies that target some of these trunk mutations already exist, and they often produce dramatic responses at first. But then resistance develops, as Bardelli found. “We're so fixated on 'the smaller the tumour gets, the better', but what one doesn't think about is what one has left behind,” Swanton says. “You're often leaving resistant clones that you can't treat.” But he thinks that by targeting multiple trunk mutations at the same time, researchers might have a shot at wiping out the cancer. Chances are slim that a single cancer cell would be able to evade a two- or three-pronged attack.
One way to do this is to use combinations of targeted therapies.