How the tumor microbiota may reduce the efficacy of cancer drugs

A recent study confirms that 5-FU exerts part of its anti-cancer effects through inhibiting the growth of F. nucleatum, the commensal associated with colorectal cancer progression.
Table of Contents

What is already know
Fusobacterium nucleatum is one of the most common bacteria in colorectal cancer tissues and has been associated with cancer progression and poorer clinical outcomes. Previous research showed that the antibiotic metronidazole can reduce tumor growth in mice that received a transplant of human colorectal cancer containing F. nucleatum. However, metronidazole also targets beneficial microbes in the gut microbiota.

What this research adds
Researchers screened 1,846 small molecules to identify inhibitors of F. nucleatum. They found that 15% of identified inhibitors were compounds used to treat cancer, such as 5-fluorouracil (5-FU). 5-FU was able to curb the growth of several F. nucleatum isolates, but it didn’t act as a broad antimicrobial. The team also found that other microbes residing in colorectal cancer tissues dampen the activity of 5-FU, and half of the tumors from colorectal cancer patients had a microbiota capable of reducing 5-FU levels.

Conclusions
The results suggest that 5-FU exerts part of its anti-cancer effects through inhibiting the growth of F. nucleatum. The findings may inform the development of new treatments for people with colorectal cancer.

Every year, more than 1 million people worldwide get colorectal cancer, one of the most common cause of cancer death. The commensal Fusobacterium nucleatum has been associated with colorectal cancer progression and poorer clinical outcomes. Now, researchers have found that a first-line drug used to treat colorectal cancer exerts part of its anti-cancer effects through curbing the growth of F. nucleatum.

The findings, published in Cell Reports, may inform the development of new treatments for people with colorectal cancer.

F. nucleatum is one of the most common bacteria found in colorectal cancer tissues, and previous research showed that the antibiotic metronidazole can reduce tumor growth in mice that received a transplant of human colorectal cancer containing F. nucleatum. However, metronidazole also targets beneficial microbes in the gut microbiota. 

To identify inhibitors of F. nucleatum with narrow spectrum activity, researchers led by Christopher Johnston and Susan Bullman at the Fred Hutchinson Cancer Center screened 1,846 small molecules from the Broad Institute’s ‘‘Bioactive Compound’’ library.

Curbing growth

The researchers identified 34 compounds that curbed the growth of F. nucleatum in culture. About half of the compounds identified are known antimicrobial drugs, and 15% are compounds used to treat cancer.

Among the compounds identified, 5-fluorouracil (5-FU) was a potent inhibitor of F. nucleatum growth. 5-FU blocked the proliferation of clinical isolates representing all four subspecies of F. nucleatum, the team found.

5-FU acts by dampening the activity of a group of enzymes that are conserved between humans and bacteria. To test whether the compound has a broad antimicrobial effect toward other microbes found in colorectal cancer tissues, the researchers measured the 5-FU sensitivity of tumor isolates of bacteria including Bacillus fragilis and Escherichia coli. All bacteria tested were resistant to 5-FU, so the researchers hypothesized that these microbes can detoxify 5-FU.

Anti-cancer efficacy

Further experiments showed that some of the microbes residing in colorectal cancer tissues, in particular E. coli, could dampen the activity of 5-FU. Half of the tumors from 6 people with colorectal cancer had a microbiota capable of reducing 5-FU levels.

These results offer support to the hypothesis that in a subset of patients with [colorectal cancer], the intratumoral microbiota harbor the ability to deplete 5-FU, which could lower chemotherapeutic efficacy,” the researchers say. 

Reducing 5-FU levels would protect both F. nucleatum and cancer cells from the drug’s toxicity, the authors add. “These findings support the benefits of taking the tumor-associated microbiota into consideration when stratifying patients into risk categories for 5-FU resistance.”