Cancer biologists find drug 5-fluorouracil works differently in different cancer types

Since the 1950s, a chemotherapy drug called 5-fluorouracil has been used to treat many types of cancer, including blood cancers and cancers of the digestive tract.

Doctors have long believed that this drug works by damaging the building blocks of DNA. However, a new study from MIT found that in colon and other gastrointestinal cancers, it kills cells by interfering with RNA synthesis.

The findings could have a significant effect on how doctors treat many cancer patients. Usually, 5-fluorouracil is given in combination with chemotherapy drugs that damage DNA, but the new study found that for colon cancer, this combination does not achieve the hoped-for synergistic effects. Instead, combining 5-FU with drugs that affect RNA synthesis could make it more effective in patients with gastrointestinal cancers, the researchers say.

“Our work is the most definitive study to date showing that RNA incorporation of the drug, leading to an RNA damage response, is responsible for how the drug works in gastrointestinal cancers ” says Michael Yaffe, the David H. Koch Professor of Science at MIT, director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research.

“The textbooks implicate drug effects on DNA as the mechanism in all cancer types, but our data shows that RNA damage is what’s really important for tumor types, like gastrointestinal cancers. intestinal, for which the drug is used clinically.”

Yaffe, the lead author of the new study, hopes to plan clinical trials of 5-fluorouracil with drugs that would enhance its harmful effects on RNA and kill cancer cells more effectively.

Jung-Kuei Chen, a researcher at the Koch Institute, and Karl Merrick, a former postdoctoral fellow at MIT, are lead authors of the paper, which appears in Cell Reports Medicine.

An unexpected mechanism

Clinicians use 5-fluorouracil (5-FU) as a first-line drug for colon, rectal, and pancreatic cancers. It is usually given in combination with oxaliplatin or irinotecan, which damage the DNA of cancer cells. The combination was thought to be effective because 5-FU can disrupt DNA nucleotide synthesis.

Without these building blocks, cells with damaged DNA would not be able to effectively repair the damage and would experience cell death.

Yaffe’s lab, which studies cell signaling pathways, wanted to further explore the underlying mechanisms of how these drug combinations preferentially kill cancer cells.

The researchers began by testing 5-FU in combination with oxaliplatin or irinotecan in colon cancer cells grown in the laboratory. To their surprise, they discovered that not only were the drugs not synergistic, but in many cases they were less effective at killing cancer cells than would be expected by simply adding up the effects of the drug. 5-FU or DNA damaging drug administered alone.

“One might have expected that these combinations would cause synergistic death of cancer cells, because you are targeting two different aspects of a common process: breaking DNA and making nucleotides,” Yaffe says.

“Karl looked at a dozen colon cancer cell lines and not only were the drugs not synergistic, but in most cases they were antagonistic. One drug seemed to cancel out what the other was doing.”

Yaffe’s lab then partnered with Adam Palmer, an assistant professor of pharmacology at the University of North Carolina School of Medicine, who specializes in analyzing data from clinical trials. Palmer’s research group looked at data from colon cancer patients who took one or more of these drugs and showed that these drugs did not have synergistic effects on survival in most patients. .

“This confirmed that when you give these combinations to patients, it is generally not the case that the drugs are actually working together in a beneficial way in an individual patient,” Yaffe says.

“Instead, it appears that one drug in the combination works well for some patients while another drug in the combination works well in other patients. We simply cannot yet predict which drug in it- same is best for which patient, so everyone gets the combination.”

These results led researchers to wonder how 5-FU worked, other than by disrupting DNA repair. Studies in yeast and mammalian cells have shown that the drug is also incorporated into the nucleotides of RNA, but there has been debate over whether this RNA damage contributes to the drug’s toxic effects on cancer cells.

Inside cells, 5-FU is broken down into two different metabolites. One of them is incorporated into DNA nucleotides and the other into RNA nucleotides. In studies of colon cancer cells, researchers found that the metabolite that interferes with RNA was much more effective at killing colon cancer cells than the one that disrupts DNA.

This RNA damage appears to primarily affect ribosomal RNA, a molecule that is part of the ribosome, a cellular organelle responsible for assembling new proteins. If cells cannot form new ribosomes, they cannot produce enough proteins to function. Additionally, the lack of intact ribosomal RNA causes cells to destroy many of the proteins that normally bind RNA to produce new functional ribosomes.

Researchers are now exploring how this ribosomal RNA damage leads cells to underprogrammed cell death, or apoptosis. They hypothesize that detecting damaged RNAs in cellular structures called lysosomes somehow triggers an apoptotic signal.

“My lab is very interested in understanding the signaling events during disruption of ribosome biogenesis, particularly in gastrointestinal cancers and even in some ovarian cancers, which cause cell death. Somehow they have to monitor the quality control of new ribosome synthesis, which is somehow connected to the death pathway machinery,” says Yaffe.

New combinations

The results suggest that drugs that stimulate ribosome production could work with 5-FU to form a highly synergistic combination. In their study, the researchers showed that a molecule that inhibits KDM2A, a suppressor of ribosome production, helped increase the rate of cell death in 5-FU-treated colon cancer cells.

The results also suggest a possible explanation for why combining 5-FU with a DNA-damaging drug often makes both drugs less effective. Some DNA-damaging drugs send a signal to the cell to stop making new ribosomes, which would reverse the effect of 5-FU on RNA.

A better approach might be to administer each drug a few days apart, allowing patients to benefit from the potential benefits of each drug without them canceling out each other.

“It’s important to note that our data does not say that these combination therapies are wrong. We know that they are clinically effective. It simply indicates that if you adjust how you administer these drugs, you could potentially improve these therapies, with relatively minor changes in when the drugs are administered,” says Yaffe.

He now hopes to work with collaborators at other institutions to conduct a phase II or III clinical trial in which patients receive the drugs on a modified schedule.

“A trial is clearly needed to look for effectiveness, but it should be simple to start because these are already clinically accepted drugs that are the standard of care for gastrointestinal cancers. All we are doing is changing the schedule with which we administer them,” he said.

The researchers also hope that their work could lead to the identification of biomarkers that predict which patients’ tumors will be more sensitive to drug combinations including 5-FU. One of these biomarkers could be RNA polymerase I, which is active when cells produce a lot of ribosomal RNA.

This story is republished courtesy of MIT News (web.mit.edu/newsoffice/), a popular site that covers news in MIT research, innovation and education.