# A Metabolites’ Interplay Can Modulate DNA Repair by Homologous Recombination

## TL;DR

This study shows that lactate and butyrate, two metabolites, can influence DNA repair and cancer drug response through opposite effects on gene expression.

## Contribution

The novel finding is the interplay between lactate and butyrate modulating DNA repair and drug response in cancer cells.

## Key findings

- Lactate and butyrate oppositely modulate DNA repair gene expression in cancer cells.
- The metabolites' interplay affects response to PARP inhibitors in pancreatic and breast cancer cells.
- The counteracting effects of these metabolites could be used to improve anticancer therapies.

## Abstract

Small molecules either derived from cell metabolic reactions or produced by gut bacterial flora have shown the potential of affecting gene expression, which suggests the possibility of interactions able to modulate cellular functions. In this context, the reported experiments were aimed at verifying a possible interplay between lactate and butyrate in modulating the efficacy of antineoplastic drugs. Butyrate is a product of gut bacterial flora, shown to be endowed with anticancer properties; conversely, increased lactate levels in cancer cells were found to be associated with higher proliferation and drug resistance. For the reported experiments, we adopted two cell lines from clinically relevant, but different cancer forms: pancreatic and triple-negative mammary adenocarcinomas. In spite of their different tissue origin, the two cell lines appeared to similarly respond to the effects of the two metabolites, which were found to modulate in opposite ways the expression of key genes involved in DNA repair by homologous recombination. As a consequence, changed efficacy of this repair pathway and modified response to PARP inhibitors were observed. Notably, our results also suggest that the counteracting effect between these two metabolites may be leveraged to address additional challenges limiting the success of anticancer therapies.