Laboratory experiments with cancer cells reveal two ways in which tumors evade drugs designed to starve and kill them, a new study shows. While chemotherapy successfully treats tumours and extends patients' lives, it is known that they do not work for everyone for long, since cancer cells rewire the mechanism by which they transform fuel into energy (metabolism) in order to avoid the treatments' effects. Many of these medications are so-called antimetabolics, which disrupt cell processes necessary for tumour growth and survival.
Led by
researchers at NYU Langone Health and its Perlmutter Cancer Center, the new
study shows how cancer cells survive in an environment made hostile by the
persistent shortage of the energy from glucose (the chemical term for blood
sugar) needed to drive tumor growth. This better understanding of how cancer
cells evade the drugs' attempts to kill them in a low-glucose environment, the
researchers say, could lead to the design of better or more effective
combination therapies.
Three
such drugs used in the study -- raltitrexed, N-(phosphonacetyl)-l-aspartate
(PALA), and brequinar -- work to prevent cancer cells from making pyrimidines,
molecules that are an essential component to genetic letter codes, or
nucleotides, that make up RNA and DNA. Cancer cells must have access to
pyrimidine supplies to produce more cancer cells and to produce uridine
nucleotides, a primary fuel source for cancer cells as they rapidly reproduce,
grow, and die. Disrupting the fast-paced but fragile pyrimidine synthesis
pathways, as some chemotherapies are designed to do, can rapidly starve cancer
cells and spontaneously lead to them dying (apoptosis).
Study
results showed that the low-glucose environment inhabited by cancer cells, or
tumor microenvironment, stalls cancer cell consumption of existing uridine
nucleotide stores, making the chemotherapies less effective.
Normally,
uridine nucleotides would be made and consumed to help make the genetic letter
codes and fuel cell metabolism. But when DNA and RNA construction is blocked by
these chemotherapies, so too is the consumption of uridine nucleotide pools,
the researchers found, as glucose is needed to change one form of uridine, UTP,
into another usable form, UDP-glucose. The irony, researchers say, is that a
low-glucose tumor microenvironment is in turn slowing down cellular consumption
of uridine nucleotides and presumably slowing down rates of cell death.
Researchers say cancer cells need to run out of pyrimidine building blocks,
including uridine nucleotides, before the cells will self-destruct.
In
other experiments, low-glucose tumor microenvironments were also unable to
activate two proteins, BAX and BAK, sitting on the surface of mitochondria, a
cell's fuel generator. Activation of these trigger proteins disintegrates the
mitochondria, and instantly sets off a series of caspase enzymes that help
initiate apoptosis (cell death).
"Our
study shows how cancer cells manage to offset the impact of low-glucose tumor
microenvironments, and how these changes in cancer cell metabolism minimize
chemotherapy's effectiveness," said study lead investigator Minwoo Nam,
PhD, a postdoctoral fellow in the Department of Pathology at NYU Grossman
School of Medicine and Perlmutter Cancer Center.
"Our
results explain what has until now been unclear about how the altered
metabolism of the tumor microenvironment impacts chemotherapy: low glucose
slows down the consumption and exhaustion of uridine nucleotides needed to fuel
cancer cell growth and hinders resulting apoptosis, or death, in cancer
cells," said senior study investigator Richard Possemato, PhD. Possemato
is an associate professor in the Department of Pathology at NYU Grossman School
of Medicine and also a member of Perlmutter Cancer Center.
Possemato,
who is also coleader of the Cancer Cell Biology Program at Perlmutter, says his
team's study results could one day be used to develop chemotherapies or
combination therapies that would change or trick cancer cells into responding
the same way in a low-glucose microenvironment as they would in an otherwise
stable glucose microenvironment.
He
also says that diagnostic tests could be developed to measure how a patient's
cancer cells would most likely respond to low-glucose microenvironments and to
predict how well a patient might respond to a particular chemotherapy.
Possemato
says his team has plans to investigate how blocking other cancer cell pathways
might trigger apoptosis in response to these chemotherapies. Some experimental
drugs, such as Chk-1 and ATR inhibitors, already exist that might accomplish
this, he notes, but more need to be investigated because Chk-1 and ATR
inhibitors are not well tolerated by patients.
For
the study, researchers performed a scan of 3,000 cancer cell genes known to be
involved in cell metabolism to determine, by deletion, which were necessary for
cancer cell survival after chemotherapy. Most of the genes they found that were
essential to cell survival in low-glucose tumor environments were also involved
in pyrimidine synthesis, a precise biological pathway targeted by many
chemotherapies. This focused their experiments on how different lab-grown
clones of cancer cells responded to low-glucose after chemotherapy and what
other chemical processes were impacted by depressed sugar levels.
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