A recent study from MIT unveils a novel mechanism of action for the chemotherapy drug 5-fluorouracil (5-FU) in gastrointestinal (GI) cancers, challenging the conventional understanding of its efficacy. The research indicates that 5-FU primarily targets RNA synthesis rather than DNA damage in colon and other GI cancers, potentially reshaping treatment strategies.
Challenging the DNA Damage Paradigm
For decades, 5-FU has been a cornerstone in treating various cancers, including blood cancers and those of the digestive tract. The prevailing belief was that 5-FU exerted its cytotoxic effects by disrupting DNA synthesis. However, Michael Yaffe, director of the MIT Center for Precision Cancer Medicine, and his team discovered that in GI cancers, 5-FU's primary mechanism involves interfering with RNA synthesis.
"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 GI cancers," said Yaffe. This finding, published in Cell Reports Medicine, suggests a need to re-evaluate how 5-FU is used in combination therapies.
Sub-Additive Effects of Traditional Combinations
The study investigated the common practice of combining 5-FU with DNA-damaging agents like oxaliplatin or irinotecan. Surprisingly, the researchers found that these combinations were not synergistic in colon cancer cells. In many instances, the combinations were less effective than either drug alone.
"One would have expected that these combinations to cause synergistic cancer cell death because you are targeting two different aspects of a shared process: breaking DNA, and making nucleotides," Yaffe explained. "Karl looked at a dozen colon cancer cell lines, and not only were the drugs not synergistic, in most cases they were antagonistic."
Analysis of clinical trial data by Adam Palmer at the University of North Carolina School of Medicine corroborated these findings, revealing a lack of synergistic survival benefits in colon cancer patients treated with these drug combinations.
RNA Damage as the Primary Driver
Further investigation revealed that 5-FU's metabolite, which interferes with RNA, was more effective at killing colon cancer cells than the one affecting DNA. This RNA damage primarily impacts ribosomal RNA (rRNA), crucial for protein synthesis. Disruption of rRNA leads to impaired ribosome biogenesis and triggers programmed cell death (apoptosis).
Implications for Future Treatment Strategies
The findings suggest that combining 5-FU with drugs that enhance ribosome production could be a more effective strategy. The researchers demonstrated that inhibiting KDM2A, a suppressor of ribosome production, increased cell death in colon cancer cells treated with 5-FU.
Moreover, the study offers a potential explanation for the reduced efficacy observed when 5-FU is combined with DNA-damaging drugs. These drugs can halt ribosome production, counteracting 5-FU's RNA-targeting mechanism. Altering the timing of drug administration could mitigate this antagonistic effect.
Clinical Trial and Biomarker Development
Yaffe is planning clinical trials to explore modified drug schedules. "A trial is clearly needed to look for efficacy, but it should be straightforward to initiate because these are already clinically accepted drugs that form the standard of care for GI cancers. All we’re doing is changing the timing with which we give them," he said.
The researchers are also seeking biomarkers, such as RNA polymerase I activity, to predict which patients will respond best to 5-FU-based combinations.
