Targeting Endoplasmic Reticulum Stress with ERX-41: A Novel Therapeutic Approach for Triple-Negative Breast Cancer

A groundbreaking study has uncovered a novel approach to combat triple-negative breast cancer (TNBC), a particularly aggressive form of breast cancer lacking targeted treatment options. The research focused on the endoplasmic reticulum stress characteristic of TNBC, which is linked to high levels of protein turnover and proliferation needs. The study highlighted the influence of specific Nuclear Receptor (NR) family members, such as the androgen receptor (AR), glucocorticoid receptor (GR), and the orphan NR tailless (TLX), in TNBC progression.

Utilizing a library of over 500 peptidomimetic compounds, the researchers developed small molecules that target and impede the interaction between oncogenes and multiple coregulators. The lead compound, ERX-41, demonstrated remarkable anti-proliferative effects on various TNBC cell lines with an IC50 range of 50-250nM. Through CRISPR/Cas9 knockout and overexpression screens, TLX was identified as ERX-41's primary target, being highly expressed in TNBC and amplified in nearly half of TNBC xenografts.

Mechanistic studies revealed that ERX-41 binds to TLX, hindering its interaction with coregulators. This interaction led to a significant decrease in TLX-activated genes and an increase in TLX-repressed genes, promoting apoptosis in TNBC models. The compound was also found to enhance endoplasmic reticulum stress, triggering autophagy and apoptosis. In vivo and ex vivo evaluations showed ERX-41's efficacy against multiple TNBC models with minimal toxicity, indicating its potential for clinical application.

The study concludes that ERX-41's dual action of blocking NR signaling and enhancing endoplasmic reticulum stress in TNBC could transform the treatment landscape for this disease. The compound's oral bioavailability and minimal side effects further underscore its promise as a therapeutic agent. The research was supported by an NIH grant and was presented at the 2018 San Antonio Breast Cancer Symposium.