Laboratory tests using cancer cells have uncovered two strategies that tumors employ to avoid treatments aimed at starving and killing them, according to a recent study.
Laboratory tests using cancer cells have uncovered two strategies that tumors employ to avoid treatments aimed at starving and killing them, according to a recent study.
While chemotherapy can be effective in treating cancer and prolonging patient survival, it doesn’t work for everyone over time. Cancer cells often adapt their metabolism—the way they generate energy—to escape the effects of these drugs. Many of these medications are classified as antimetabolics, which interfere with the processes necessary for the growth and survival of tumors.
In the study, three specific drugs—raltitrexed, N-(phosphonacetyl)-l-aspartate (PALA), and brequinar—aim to halt the production of pyrimidines. Pyrimidines are vital molecules for constructing genetic codes—nucleotides that form RNA and DNA. Cancer cells require a continuous supply of pyrimidines to proliferate and create uridine nucleotides, which serve as essential energy sources enabling rapid cell division and growth. By disrupting the intricate synthesis pathways of pyrimidines, these chemotherapies can quickly deplete cancer cells’ resources, subsequently leading to their death (apoptosis).
The research, led by scientists at NYU Langone Health and its Perlmutter Cancer Center, provides insights into how cancer cells can thrive in a hostile environment characterized by limited glucose (the sugar in the blood) vital for tumor growth. Understanding how these cells evade the lethal effects of chemotherapy in low-glucose conditions may pave the way for more effective combination treatments.
Published in *Nature Metabolism* on November 26, the study revealed that the low-glucose environments encountered by cancer cells hinder their use of uridine nucleotide reserves, rendering chemotherapy less potent.
Typically, uridine nucleotides would be synthesized and utilized in the creation of genetic codes and for fueling cellular metabolism. However, when chemotherapy blocks the synthesis of DNA and RNA, it also inhibits the usage of uridine nucleotide stores because glucose is necessary for converting one type of uridine, UTP, into another usable form, UDP-glucose. Researchers noted the irony that a low-glucose tumor environment simultaneously slows down the consumption of uridine nucleotides, likely delaying cell death. Cells need to deplete their pyrimidine resources, which includes uridine nucleotides, before they will trigger self-destruction.
Additional experiments indicated that low-glucose tumor environments fail to activate two specific proteins, BAX and BAK, located on mitochondria, the cell’s powerhouses. When activated, these proteins disrupt mitochondria and trigger a cascade of caspase enzymes that promote apoptosis (cell death).
“Our study demonstrates how cancer cells counter the effects of low-glucose environments and how changes in their metabolism diminish the effectiveness of chemotherapy,” stated Minwoo Nam, PhD, the lead investigator and postdoctoral fellow in the Department of Pathology at NYU Grossman School of Medicine and Perlmutter Cancer Center.
“Our findings clarify the previously unclear relationship between the altered metabolism of tumor environments and chemotherapy: low glucose hampers the depletion and utilization of uridine nucleotides essential for cancer cell growth, thereby limiting apoptosis within these cells,” explained senior study investigator Richard Possemato, PhD, an associate professor in the Department of Pathology at NYU Grossman School of Medicine and also a member of Perlmutter Cancer Center.
Possemato, who co-leads the Cancer Cell Biology Program at Perlmutter, notes that the results of his team’s study could eventually lead to the creation of chemotherapies or combination therapies that trick cancer cells into reacting in low-glucose conditions as they would in stable glucose settings.
He also mentions the potential for developing diagnostic tools that could assess how a patient’s cancer cells would likely respond to low-glucose conditions and forecast their responses to specific chemotherapy treatments.
Plans are in place to explore how inhibiting other cancer cell pathways might provoke apoptosis in response to these chemotherapies. There are experimental drugs, like Chk-1 and ATR inhibitors, that could achieve this; however, the team recognizes that more options need investigation since these particular inhibitors are not well tolerated by patients.
For this study, researchers screened 3,000 cancer cell genes associated with cell metabolism to identify which ones were crucial for survival following chemotherapy. Many of the genes essential for surviving in low-glucose tumor environments were linked to pyrimidine production, a targeted pathway by several chemotherapies. This directed their experiments toward analyzing how different lab-grown cancer cell clones reacted to low-glucose conditions after exposure to chemotherapy.
The study received funding from multiple National Institutes of Health grants and additional financial support from the Pew Charitable Trusts, Alexander and Margaret Stewart Trust, and the American Cancer Society.
Alongside Nam and Possemato, other researchers from NYU Langone involved in this study include co-investigators Wenxin Xia, Abdul Hannan Mir, and Tony Huang.
