Will Chemo Work for You?

There’s a lot of research these days aimed at identifying characteristics of cancer cells that make them susceptible to particular treatments, as breast-cancer cells with extra expression of the her2 protein are treatable with Herceptin. Equally important, it seems to me, is identifying cancers that will not respond to standard chemo, which can be hugely debilitating. It would be a great help to patients if doctors could tell before administering a single dose whether the chemo will help.

Now scientists at MIT have shown, in a paper in the online edition of the journal Genes and Development, that 48 specific genes explain a good deal of the variation in whether malignant cells will be killed by chemo.

The old-line chemo drugs, such as those based on platinum compounds such as oxaliplatin, work by damaging DNA. That prevents malignant cells from multiplying. But the MIT scientists find that a group of 48 genes can predict how susceptible a patient is to a toxic compound called MNNG that, like common chemo agents, kills cells by inducing irreparable DNA damage. Which of the 48 genes someone has produces huge variability in response to DNA-damaging compounds. “A cell line from one person would be killed dramatically, while that from another person was resistant to exposure,” said Rebecca Fry, former MIT research scientist and lead author of the paper who is now at the University of North Carolina School of Public Health. “It wasn’t known that cell lines from different people could have such dramatic differences in responses.”

MNNG (N-methyl-N-nitro-N-nitrosoguanidine) causes DNA lesions, leading to cell death. But MNNG can also turn on genes that repair DNA. The net result—cell death or not—seems to reflect the interplay of biochemical pathways controlled by the 48 genes. After measuring the expression of every gene in each cell line, the scientists could predict from the expression of just 48 whether MNNG would kill cells, with 94 percent accuracy. Now the push is on to predict individuals’ responses to cisplatin, a common chemotherapy agent, and temozolomide, used to treat brain cancer. It’s exactly the kind of advance that critics of the war on cancer—with its focus on elucidating basic biology rather than discoveries useful to patients—are calling for.