Authors
Zenaida Fuentes, Gaurav Sharma, Bianca A Romo, Rahul Gopalam, Khaled Mohamed Nassar, Paulina Ramirez, Nicole Mejia, Chia-Yuan Chen, Scott Elmore, Henry Neal, Harika Nagandla, Panneerdoss Subbarayalu, Uday P Pratap, Christoforos Thomas, Jung-Mo Ahn, Ganesh V Raj, Suryavathi Viswanadhapalli, Ratna K Vadlamudi
Published in
Biomolecules. Volume 16. Issue 3. Mar 23, 2026. Epub Mar 23, 2026.
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.
PMID:
41897416
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.
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