# Growth factors maintain intratumoral heterogeneity and drive therapeutic resistance in triple-negative breast cancer

## TL;DR

This study shows that growth factors like HGF and NRG1 help triple-negative breast cancer resist treatment and maintain tumor diversity.

## Contribution

The paper reveals that growth factors maintain tumor heterogeneity and resistance to trametinib in TNBC.

## Key findings

- HGF and neuregulin 1 drive therapeutic resistance in TNBC.
- HGF inhibitors can restore sensitivity to trametinib.
- High HGF expression in patients correlates with poor outcomes and increased mesenchymal markers.

## Abstract

Triple-negative breast cancer (TNBC) shows considerable intratumoral heterogeneity, which contributes to therapeutic resistance. Recent studies show that targeted therapeutics can steer TNBC toward homogeneous, drug-resistant states, but little is understood about how the microenvironment modulates these responses. We report studies to determine how components of the microenvironment impact response to trametinib and cellular heterogeneity. We find that multiple microenvironmental factors, including HGF and neuregulin 1, can drive therapeutic resistance and that treatment with hepatocyte growth factor (HGF) inhibitors restores trametinib sensitivity. Interestingly, treatment with these ligands reverses trametinib-induced homogeneity, restoring heterogeneity to levels comparable to baseline both in vitro and in vivo. Analysis of patient data demonstrates that TNBC with high HGF expression levels has a poor outcome and increased expression of basal and mesenchymal state markers. Our data suggest that common growth factors drive therapeutic resistance and maintain tumor heterogeneity in TNBC, and that co-targeting these factors may improve therapeutic response.

Devlin et al. demonstrate that growth factors like HGF and NRG1 can cause resistance to targeted inhibitors like trametinib in TNBC. These growth factors function by maintaining low levels of proliferation as well as the intratumoral heterogeneity that is characteristic of TNBC.