# Targeting LIPA with ERX-41 Induces ER Stress and Inhibits Tumor Progression in Inflammatory Breast Cancer

## TL;DR

A new drug called ERX-41 targets LIPA to increase ER stress in inflammatory breast cancer cells, potentially offering a novel treatment for this aggressive cancer subtype.

## Contribution

ERX-41 is a novel small molecule that targets LIPA to induce ER stress and inhibit tumor progression in inflammatory breast cancer.

## Key findings

- ERX-41 significantly reduced IBC cell viability and clonogenic survival while promoting apoptosis.
- ERX-41 treatment activated ER stress markers and reduced tumor volume in KPL4 xenografts.
- LIPA inhibition with ERX-41 was confirmed to be specific and therapeutically actionable in IBC models.

## Abstract

Approximately 2–4% of all breast cancer cases are inflammatory breast cancer (IBC), an extremely rare and severe subtype of the disease. Current therapies, including chemotherapy, surgery, and radiotherapy, remain insufficient, underscoring the need for novel therapeutic approaches. IBC exhibits elevated basal endoplasmic reticulum (ER) stress, suggesting a potential vulnerability. We recently developed ERX-41, a small molecule that exacerbates ER stress in cancer cells by inhibiting the endoplasmic reticulum-localized function of Lysosomal acid lipase A (LIPA). Here, we evaluated the therapeutic potential of ERX-41 in IBC models. ERX-41 markedly reduced the viability of IBC cells and significantly impaired clonogenic survival while promoting apoptosis. The specificity of ERX-41 was confirmed using LIPA-knockdown and LIPA-knockout cells. RT-PCR-based assays revealed rapid induction of XBP1 splicing within 6 h of treatment, and Western blot analyses demonstrated activation of ER stress markers including CHOP, PERK, and ATF4. In KPL4 xenografts, ERX-41 treatment significantly decreased tumor volume, accompanied by reduced proliferation and increased ER stress marker expression by IHC. Collectively, these findings identify LIPA as a therapeutically actionable vulnerability in IBC and establish ERX-41 as a potential drug for IBC.