The study shows how cancer cells adapt to a low-glucose environment, resist chemotherapy by preserving uridine nucleotides and avoiding apoptosis. New research reveals two strategies tumors use to evade drugs designed to starve and kill them, as demonstrated in laboratory experiments with cancer cells.

Although chemotherapy is successful in treating cancer and prolonging patients’ lives, it is known to not work for long on everyone because cancer cells change the process that converts fuel into energy (metabolism) in order to overcome the effects of the drugs. Many of these drugs are called antimetabolites, which disrupt cellular processes essential for tumor growth and survival.

Three such drugs used in the study — raltitrexed, N-(phosphoacetyl)-l-aspartate (PALA), and brequinar — work to prevent cancer cells from producing pyrimidines, molecules or nucleotides that are a key component of their genetic letter code. It creates RNA and DNA. Cancer cells need to access pyrimidine stores to create more cancer cells and produce uridine nucleotides, which are cancer cells’ primary fuel source as they rapidly proliferate, grow, and die. Disruption of the rapid but delicate pathways of pyrimidine synthesis enhanced by some chemotherapeutics can rapidly starve cancer cells and cause them to die spontaneously (apoptosis).

New research led by researchers at NYU Langone Health and Perlmutter Cancer Center shows how cancer cells survive in a hostile environment due to a constant lack of energy from glucose (the chemical term for blood sugar) needed to fuel tumor growth. A better understanding of how cancer cells evade attempts by drugs to kill them in a low-glucose environment could lead to the development of better or more effective combination treatments, the researchers said.

Low glucose environment and resistance to cancer

Research results published in an online journal Nature Metabolism The research, conducted Nov. 26, showed that the low-glucose environment, or tumor microenvironment, in which cancer cells live prevents cancer cells from depleting available stores of uridine nucleotides, making chemotherapy less effective.

Uridine nucleotides are normally produced and consumed to help establish genetic letter codes and fuel cell metabolism. But the researchers found that when DNA and RNA structure were blocked by this chemotherapy, depletion of uridine nucleotide pools was also blocked because glucose is needed to convert one form of uridine, UTP, into another usable form, UDP-glucose. The irony, the researchers say, is that the low-glucose tumor microenvironment slows cells’ consumption of uridine nucleotides, possibly slowing the rate of cell death. Researchers say cancer cells must run out of pyrimidine building blocks, including uridine nucleotides, before the cells self-destruct.

In other experiments, the low-glucose tumor microenvironment also failed to activate two proteins (BAX and BAK) found on the surface of mitochondria, the cell’s fuel generator. Activation of these trigger proteins breaks down the mitochondria and triggers a series of caspase enzymes that help initiate immediate apoptosis (cell death).

Implications for future treatments

“Our study shows how cancer cells manage to compensate for the effects of the low-glucose tumor microenvironment and how these changes in cancer cell metabolism minimize the effectiveness of chemotherapy,” said lead investigator Minwoo Nam, a postdoctoral researcher in the Department of Science. Pathology at New York Grossman School of Medicine and Perlmutter Cancer Center.

“Our results shed light on what has been hitherto unclear about how the altered metabolism of the tumor microenvironment affects chemotherapy: low glucose slows the consumption and depletion of uridine nucleotides, which are necessary to promote cancer cell growth, and prevents apoptosis, or cancer cell death,” said senior investigator Richard Possemato, Ph.D. Possemato is an associate professor of pathology at NYU Grossman School of Medicine and a member of the Perlmutter Cancer Center.

Possemato, who is also co-director of the Cancer Cell Biology Program at Perlmutter, says his team’s findings could one day be used to develop chemotherapy or combination treatments that cause or alter the way cancer cells respond to low glucose in the same way. The microenvironment is as in a stable glucose microenvironment.

It’s also possible to develop diagnostic tests to measure how a patient’s cancer cells will respond to a low-glucose microenvironment and predict how well the patient might respond to certain chemotherapy, he says.

Possemato said his team plans to investigate how blocking other pathways in cancer cells might trigger apoptosis in response to this chemotherapy. He notes that some experimental drugs, such as Chk-1 and ATR inhibitors, are already available that can achieve this, but more research is needed because Chk-1 and ATR inhibitors are not well tolerated by patients.

For the study, researchers screened 3,000 cancer cell genes known to be involved in cellular metabolism to identify by deleting genes that are essential for cancer cells to survive chemotherapy. Many of the genes they found to be important for cell survival in low-glucose tumor environments were also involved in pyrimidine synthesis, a precise biological pathway targeted by many chemotherapies. This focused his experiments on how different laboratory-grown cancer cell clones responded to low glucose levels after chemotherapy and what other chemical processes were affected by low sugar levels.