In a notable shift from long-held beliefs, researchers at MIT have unveiled surprising findings about the action of an old cancer drug, 5-fluorouracil (5-FU), commonly used in the treatment of various cancers since the 1950s. While it was previously assumed that the drug’s effectiveness against cancer was due to its impact on DNA synthesis, MIT’s recent study discovered its primary mechanism in gastrointestinal cancers involves interference with RNA synthesis instead.
According to a report from MIT, this revelation came after scientists observed that the typically prescribed combination of 5-FU with DNA-damaging chemotherapy drugs wasn’t achieving the expected synergistic effects in colon cancer treatments. The study's senior author, Michael Yaffe, a David H. Koch Professor of Science at MIT and the director of the MIT Center for Precision Cancer Medicine, explained, "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."
The research team's curiosity was piqued when data analysis, led by Yaffe's lab and in partnership with UNC School of Medicine's pharmacology assistant professor Adam Palmer, showed no significant survival benefit in patients when 5-FU was combined with DNA-targeting drugs. As per the information from the MIT, this lack of synergy was explained by the fact that RNA interference rather than DNA repair disruption is predominantly how 5-FU operates in the context of gastrointestinal cancers. The implications of these findings are vast, potentially altering how combinations of cancer medication are deployed in the clinical setting.
Delving into the cellular impact, researchers found that ribosomal RNA, critical in protein assembly, is mainly affected by 5-FU's RNA-damaging properties. "My lab is very interested in trying to understand the signaling events during disruption of ribosome biogenesis," Yaffe told MIT News. This research pursuit could eventually inform treatment protocols, ideally leading to more effective cancer therapies by pairing 5-FU with drugs that enhance its RNA-affecting capabilities.
The MIT team is currently advocating for clinical trials to examine the efficacy of administering 5-FU in concert with agents that stimulate ribosome production, potentially amplifying the drug's cancer-killing abilities. Additionally, the possibility of adjusting the timing of administering 5-FU in relation to other drugs could help avoid negating effects and improve patient outcomes. "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," Yaffe emphasizes, as noted by MIT News.
As scientists work towards identifying biomarkers that might predict patient responsiveness to 5-FU-inclusive drug combinations, the research supported by the Damon Runyon Cancer Research Fund and several other foundations continues to shape our understanding of cancer pharmacology and pave the way for more tailored, effective treatment regimens.