Description
Triple negative breast cancers (TNBC) are associated with poor clinical outcomes due to a lack of targeted therapies. Here, we identified a small molecule ERX-41 with potent activity against TNBC cell lines, primary tumor explants and xenografts. ERX-41 induced endoplasmic reticulum (ER) stress and caused cell death. We identified lysosomal acid lipase A (LIPA) gene as the molecular target for ERX-41 and critical for ERX-41 to induce ER stress and cell death. Mechanistically, interaction of ERX-41 with LIPA alters expression of multiple ER-resident proteins involved in protein folding. Importantly, we defined that ER localization of LIPA but not its lipase function are necessary for ERX-41 activity in TNBC. Our study implicates a new targeted strategy for multiple solid tumors, including breast, brain, pancreatic and ovarian, whereby a small orally bioavailable molecule (ERX-41) targeting LIPA blocks protein folding, induces ER stress and causes cell death.
[doi:10.25345/C5DR2PC8N]
[dataset license: CC0 1.0 Universal (CC0 1.0)]
Keywords: Cell death ; Endoplasmic reticulum stress ; LIPA ; Small molecule ; Triple neggative breast cancer
Contact
Principal Investigators:
(in alphabetical order)
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Ratna K Vadlamudi, Ph.D., UT Health San Antonio, United States
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stweintraub
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