Chemotherapies are proven to effectively treat cancers and extend patients’ lives. However, they don’t work for everyone as cancer cells rewire the process by which they convert fuel into energy (metabolism) to outmaneuver the drugs’ effects.
Many cancer drugs are antimetabolites, which interfere with the cellular processes necessary for tumor growth and survival. The study focuses on three such drugs—raltitrexed, N-(phosphonacetyl)-l-aspartate (PALA), and brequinar—that prevent cancer cells from producing pyrimidines.
Pyrimidines are essential molecules for forming RNA and DNA, which are crucial for cell division and cancer cell proliferation. By disrupting pyrimidine synthesis, these drugs starve cancer cells, impeding their ability to grow and reproduce and triggering their death (apoptosis).
A study by NYU Langone Health and its Perlmutter Cancer Center researchers reveals how cancer cells survive in low-glucose environments, which is common in tumors.
In their study, researchers scanned 3,000 cancer cell genes related to cell metabolism to identify which ones were essential for cancer cell survival following chemotherapy. By selectively deleting genes, they found that most of the key genes involved in survival under low-glucose conditions were also part of the pyrimidine synthesis pathway targeted by many chemotherapies.
This discovery led the researchers to focus their experiments on how various lab-grown clones of cancer cells responded to low-glucose environments after chemotherapy and to explore which other biological processes were affected by the reduced sugar levels.
The research shows that the glucose shortage in the tumor microenvironment prevents cancer cells from using their existing stores of uridine nucleotides, which are essential for cell growth. This stalls the effectiveness of chemotherapies that target pyrimidine synthesis. Understanding how cancer cells evade treatment in low-glucose conditions could help develop better combination therapies for more effective cancer treatment.
In a normal cellular process, uridine nucleotides are produced and consumed to help build genetic material and fuel cell metabolism. However, when chemotherapies block DNA and RNA synthesis, they also halt the consumption of uridine nucleotide pools. This is because glucose is needed to convert one form of uridine, UTP, into a usable form, UDP-glucose.
The study found that in low-glucose tumor microenvironments, the reduced glucose availability slows down the consumption of uridine nucleotides, reducing cell death. Cancer cells require depleting pyrimidine building blocks, including uridine nucleotides, before they undergo self-destruction.
Additionally, in low-glucose environments, tumor cells failed to activate two proteins, BAX and BAK, located on the surface of mitochondria. Normally, the activation of these proteins causes mitochondria to disintegrate, triggering a cascade of caspase enzymes that initiate apoptosis (cell death).
Study lead investigator Minwoo Nam, PhD, a postdoctoral fellow in the Department of Pathology at NYU Grossman School of Medicine and Perlmutter Cancer Center, said, “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.”
Senior study investigator Richard L. Possemato, PhD. Dr. Possemato, an associate professor in the Department of Pathology and also a member of Perlmutter Cancer Center, said, “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.”
“The 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.”
“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.”
Dr. Possemato says his team has plans to investigate how blocking other cancer cell pathways might trigger apoptosis in response to these chemotherapies. He notes that some experimental drugs, such as Chk-1 and ATR inhibitors, might accomplish this, but more need to be investigated because patients do not tolerate Chk-1 and ATR inhibitors.
Journal Reference:
- Nam, M., Xia, W., Mir, A.H. et al. Glucose limitation protects cancer cells from pyrimidine restriction and replication inhibition-induced apoptosis. Nat Metab (2024). DOI: 10.1038/s42255-024-01166-w