# Epacadostat and Olaparib Synergistically Inhibit the Growth of BRCA-Proficient Triple-Negative Breast Cancer by Suppressing the Expression of BRCA1 and RAD51

## TL;DR

Combining Epacadostat and Olaparib effectively inhibits the growth of BRCA-proficient triple-negative breast cancer by reducing DNA repair capabilities.

## Contribution

The study reveals a novel synergistic mechanism involving IDO1 and PARP1/2 inhibition that reduces HR gene expression in BRCA-proficient TNBC.

## Key findings

- Epacadostat and Olaparib together significantly reduce the proliferation of BRCA-proficient TNBC cells.
- The combination increases DNA damage and apoptosis by reducing NAD+ and kynurenine levels and increasing ROS.
- Dual inhibition of IDO1 and PARP1/2 reduces the expression of BRCA1 and RAD51, impairing DNA repair.

## Abstract

Triple-negative breast cancer (TNBC) cells with intact homologous recombination (HR) repair mechanism can survive treatment with Olaparib, which further limits the clinical application of PARP1/2 inhibitors. Previous studies have demonstrated that inhibition of indoleamine 2,3-dioxygenase (IDO) can enhance the sensitivity of human tumor cells to PARP1/2 inhibitors. However, the mechanisms underlying their synergistic effects in the treatment of TNBC remain unclear. Herein, we demonstrate that the combination of Olaparib and Epacadostat significantly reduces the proliferation of BRCA-proficient MDA-MB-231 and MDA-MB-468 cells compared to either monotherapy. Mechanistically, Epacadostat reduces intracellular kynurenine and NAD+ levels, thereby sensitizing TNBCs to PARP1/2 inhibition and significantly amplifying Olaparib-induced DNA damage. Furthermore, Epacadostat and Olaparib synergistically increase cellular reactive oxygen species (ROS), leading to DNA oxidative damage and apoptosis. In vivo, Epacadostat and Olaparib significantly suppressed MDA-MB-468 tumor growth compared to the monotherapy groups, while promoting an increase in phosphorylated H2AX. Notably, the dual inhibition of IDO1 and PARP1/2 specifically reduced the expression of HR core genes and proteins, such as BRCA1 and RAD51, which may contribute to impaired DNA-damage repair and increased sensitivity to Olaparib. In summary, targeting both IDO1 and PARP1/2 represents a promising combination therapy for BRCA-proficient TNBC.