Doctors have traditionally thought that the chemotherapy drug 5-fluorouracil (5-FU) functions by damaging DNA. However, new research reveals that for some cancer types, it actually kills cells by disrupting RNA production. This discovery may aid scientists in creating more effective drug combinations for colon and gastro-intestinal cancers.
Since the 1950s, 5-fluorouracil has been a go-to chemotherapy treatment for various cancers, including blood and digestive cancers.
For years, it has been assumed that 5-FU operates by harming DNA’s building blocks. But a recent study from MIT demonstrated that, particularly in colon and other gastrointestinal cancers, it kills cancer cells by affecting RNA synthesis.
This research could significantly alter treatment approaches for many cancer patients. Typically, 5-fluorouracil is used with chemotherapy drugs that damage DNA, but the study discovered that in colon cancer, this combination fails to deliver the expected synergistic benefits. Instead, pairing 5-FU with medications that alter RNA synthesis may enhance its effectiveness for patients with GI cancers, according to the researchers.
“Our study is the most comprehensive to date showing that the incorporation of the drug into RNA, leading to an RNA damage response, is key to its efficacy in gastrointestinal cancers,” explains Michael Yaffe, a professor of science at MIT and director of the MIT Center for Precision Cancer Medicine. “Textbooks have attributed the drug’s actions to DNA effects across all cancer types, but our findings indicate that RNA damage is crucial for tumors like GI cancers where the drug is typically used.”
Yaffe, the study’s senior author, aims to design clinical trials that combine 5-fluorouracil with agents that enhance its RNA-targeting abilities, potentially leading to better outcomes for cancer patients.
Research scientist Jung-Kuei Chen and former MIT postdoc Karl Merrick are the primary authors of the paper, which will be published in Cell Reports Medicine.
An unexpected mechanism
5-fluorouracil (5-FU) serves as a first-line treatment for cancers of the colon, rectum, and pancreas, often paired with oxaliplatin or irinotecan, which cause DNA damage in cancer cells. This combination was believed to work due to 5-FU’s ability to hinder DNA nucleotide synthesis. If cells cannot access these necessary components, their damaged DNA can’t repair itself, leading to cell death.
Yaffe’s lab, focusing on cell signaling pathways, sought to look deeper into the mechanisms by which these drug combinations selectively destroy cancer cells.
The researchers tested 5-FU alongside either oxaliplatin or irinotecan in colon cancer cells in the lab. Surprisingly, they found that instead of working together, in many cases, the drugs were less effective than anticipated when considered individually.
“It was expected that these combinations would create a synergistic impact on cancer cell death by targeting different aspects of a shared process: DNA breakdown and nucleotide creation,” Yaffe notes. “Karl studied several colon cancer cell lines, and rather than being synergistic, they were antagonistic. One drug appeared to counteract the effects of the other.”
Yaffe’s lab collaborated with Adam Palmer, an assistant professor at the University of North Carolina School of Medicine who specializes in clinical trial data analysis. Palmer’s team reviewed data from colon cancer patients treated with these medications and found that the drugs generally did not display synergistic survival benefits.
“This confirmed that administering these combinations doesn’t usually result in the expected beneficial collaboration between the drugs for individual patients,” Yaffe states. “Instead, one drug may be effective for some patients, while another might work better for others. Unfortunately, we still cannot predict which drug will be most beneficial for each patient, which leads to a default combination treatment for everyone.”
These outcomes prompted the researchers to reconsider how 5-FU functions if it doesn’t primarily disrupt DNA repair. Previous studies in yeast and mammalian cells indicated that the drug is also incorporated into RNA nucleotides, but there was disagreement on the role this RNA damage plays in its toxic effects on cancer cells.
Inside the cells, 5-FU is metabolized into two distinct compounds: one that integrates into DNA nucleotides and another that incorporates into RNA nucleotides. The researchers discovered that the RNA-interfering metabolite particularly damages colon cancer cells more effectively than the DNA-disrupting one.
The RNA damage primarily affects ribosomal RNA, which is a component of the ribosome—a cell organelle critical for protein assembly. Without the ability to form new ribosomes, cells struggle to produce the proteins needed for survival. Furthermore, damaged ribosomal RNA leads cells to degrade several proteins that typically assist in creating new functional ribosomes.
The researchers are currently investigating how this ribosomal RNA damage causes cells to undergo programmed cell death or apoptosis. They propose that the presence of damaged RNAs in cell structures called lysosomes may trigger an apoptotic signal.
“My lab aims to unravel the signaling mechanisms involved in ribosome biogenesis disruption, particularly concerning GI and some ovarian cancers that induce cell death,” Yaffe explains. “Somehow, there seems to be a quality control measure for new ribosome synthesis interconnected with the pathways that lead to cell death.”
New combinations
The study suggests that medications that promote ribosome production could work synergistically with 5-FU. The researchers successfully demonstrated that a molecule inhibiting KDM2A, a ribosome production suppressor, increased cell death rates in colon cancer cells treated with 5-FU.
The findings also shed light on why combining 5-FU with DNA-damaging agents often diminishes the effectiveness of both drugs. Some DNA-targeting medications signal the cell to halt ribosome production, counteracting 5-FU’s impact on RNA. A potentially more effective plan could involve administering the drugs a few days apart, allowing patients to gain the advantages of each treatment without negating one another.
“Crucially, our findings do not imply that these combination therapies are ineffective; clinical efficacy is well-documented. Rather, they suggest that adjusting the administration timing of these therapies could enhance their effectiveness with minor modifications,” Yaffe explains.
He is eager to collaborate with other institutions to initiate phase 2 or 3 clinical trials where patients will receive these drugs on a revised schedule.
“A trial is indeed warranted to assess efficacy, but the initiation should be straightforward given that these are established drugs currently part of the standard care for GI cancers. All we are doing is tweaking the timing,” he remarks.
The researchers also aspire that their findings may lead to identifying biomarkers that can predict how receptive a patient’s tumor will be to combinations including 5-FU. One potential biomarker could be RNA polymerase I, which is active when cells produce a significant amount of ribosomal RNA.
This research received funding from the Damon Runyon Cancer Research Fund, a Ludwig Center at MIT Fellowship, the National Institutes of Health, the Ovarian Cancer Research Fund, the Holloway Foundation, and the STARR Cancer Consortium.
