Why chemo works for some people and not others
MIT cell findings could predict individuals' responses
Anne Trafton, News Office
September 18, 2008
MIT researchers have shown that cells from different people don't all react
the same way when exposed to the same DNA-damaging agent -- a finding that
could help clinicians predict how patients will respond to chemotherapy.
The research team from MIT's Center for Environmental Health Sciences (CEHS)
and the Departments of Biological Engineering and Biology, identified a group
of 48 genes that can predict how susceptible an individual is to the toxic
compound known as MNNG. The work appears in the Sept. 18 online edition of
Genes and Development.
MNNG, a DNA-damaging compound similar to toxic chemicals found in tobacco
smoke and in common chemotherapy agents, usually kills cells by inducing irreparable
DNA damage. However, the researchers found a wide range of susceptibility among
cells taken from healthy people.
"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. "It wasn't known that cell lines from
different people could have such dramatic differences in responses."
Toxic agents such as MNNG create lesions in DNA, provoking the cell to defend
itself with a variety of DNA-repair and other pathways. However, every individual
expresses slight differences in the genes involved in those pathways.
"Even if everyone is exposed to exactly the same things, they would respond
differently, because we're all genetically different," said Leona Samson, senior
author of the paper, director of CEHS, and an American Cancer Society Research
The team members found that after measuring the expression of every gene in
each cell line, they could predict cell sensitivity to MNNG from the expression
of just 48 specific genes, with 94 percent accuracy.
Several of those 48 genes have already been linked to cancer, said Samson,
but it was not known that their expression is already altered before exposure
to the DNA damaging agent.
This study is specific to MNNG, but similar efforts are now underway in Samson's
lab to predict individuals' responses to other toxic agents, including cisplatin,
a common chemotherapy agent, and temozolomide, used to treat brain cancer.
Fry, the lead author of the paper, is now an assistant professor at the University
of North Carolina School of Public Health. Other authors are Peter Svensson,
a postdoctoral fellow in CEHS; Chandni Valiathan, a graduate student in computational
and systems biology; Emma Wang and Brad Hogan, technical assistants in CEHS;
Sanchita Bhattacharya, former CEHS research scientist; James Bugni, former
CEHS postdoctoral fellow; and Charles Whittaker, a research scientist in the
David H. Koch Institute for Integrative Cancer Research.
The research was funded by the National Institute of Environmental Health
Sciences and the National Cancer Institute.
A version of this article appeared in MIT
Tech Talk on September
24, 2008 (download PDF).