cancer (TNBC) is notoriously aggressive and is difficult to treat because its
cells lack the targetable receptors found in other forms of breast
Only about 30% of TNBC patients achieve a pathologic
complete response, or a complete eradication of active cancer cells,
following chemotherapy. Those who do frequently relapse shortly
‘Triple-negative breast cancer cells ramp up production of a key component of DNA in response to chemotherapy. Targeting this pathway could undermine their resistance to such therapies.’
A team of researchers led by Alex Toker of the Ludwig Center at
Harvard has discovered a metabolic weakness in triple-negative breast
cancer (TNBC) cells that may be exploited to quell their resistance to
"Trying to understand the mechanisms that contribute to cancer's
resistance to therapy is a major mission here at the Ludwig Center at
Harvard," said Alex Toker.
In the new study, published online in the journal Cancer Discovery
Toker, an investigator at the Ludwig Center at Harvard Medical School,
and his team including lead author Kristin Brown, formerly of the Ludwig
Center at Harvard and now at Peter MacCallum Cancer Center in
Melbourne, Australia, outline a newly discovered chink in the armor of
TNBC cells. This "metabolic vulnerability" can be used to circumvent
The scientists demonstrated that chemotherapy effectively reprograms
TNBC cells to ramp up production of the pyrimidine nucloetides, key
building blocks of DNA. This heightens the cells' DNA repair abilities
and ultimately results in greater resistance to chemotherapies that work
by damaging the DNA of rapidly dividing cells.
"This actually makes sense if you think about it, because if a tumor
cell is going to repair DNA and therefore evade the death-inducing
effects of chemotherapy, the only way they can really do that is by
rebuilding DNA, and the only way to rebuild DNA is to make more
nucleotides," Toker said.
Toker and his team reasoned that blocking the pyrimidine synthesis
pathway in TNBC cells would hinder their DNA repair abilities and make
them more susceptible to the DNA-damaging effects of chemotherapy. To
test this hypothesis, the team exposed TNBC cells in the lab to a drug
combination of doxorubicin, a commonly used chemotherapy agent, and
leflunomide, a known inhibitor of dihydroorotate dehydrogenase (DHODH), a
crucial enzyme in the biochemical reactions that generate pyrimidines.
"One of the major reasons we chose leflunomide is because we wanted a
rapid path to clinical impact, and leflunomide is already FDA-approved
and widely used to treat autoimmune diseases such as rheumatoid
arthritis," Toker said.
Toker's group found that leflunomide blocked the increase of
pyrimidine nucleotides in TNBC cells, thus impairing their ability to
repair the DNA damage dealt by doxorubicin, and resulting in increased
cancer cell death.
The scientists then repeated the experiment in mice that had been
transplanted with human TNBC cells. "We found that treating the mice
with doxorubicin or leflunomide alone only slowed tumor growth, but that
a combination therapy involving both drugs resulted in significant
tumor regression," Toker said.
Importantly, the combination therapy in mice did not cause any
weight loss or gain in the animals - an indication that the drug regimen
might be reasonably well-tolerated in humans.
"One of the things we would like to do is develop clinical trials in
patients with this combination strategy, whether it be with leflunomide
or some other drugs that are coming online that might have better
pharmacological properties in patients," Toker said.
In the meantime, Toker said his group is moving forward with plans
to investigate the molecular basis of increased pyrimidine biosynthesis
in TNBC cells.
"There is something about this pathway in triple negative breast
cancer that is especially important," Toker said. "We don't know what
the genetic basis underlying it is, but it's something we would really
like to find out."