Study reveals how cancer cells evade chemotherapy in low-glucose environments

Laboratory experiments with cancer cells reveal two ways in which tumors evade drugs designed to starve and kill them, a new study shows.

While chemotherapies successfully treat cancers and extend patients' lives, they are known not to work for everyone for long, as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs' effects. Many of these drugs are so-called antimetabolics, disrupting cell processes needed for tumor growth and survival.

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).

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.

Publishing in the journal Nature Metabolism online Nov. 26, 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."

Minwoo Nam, PhD, study lead investigator, 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.

Funding support for the study was provided by National Institutes of Health grants P30CA016087, R01CA286141, R01CA214948, R01GM132491, R35GM139610. Additional funding support came from the Pew Charitable Trusts, Alexander and Margaret Stewart Trust, and the American Cancer Society.

Besides Nam and Possemato, other NYU Langone researchers involved in this study are co-investigators Wenxin Xia, Abdul Hannan Mir, and Tony Huang.