MassIVE MSV000089091

Partial Public PXD032693

Targeting LIPA Independent of its Lipase Activity is a Therapeutic Strategy in Solid Tumors via Induction of Endoplasmic Reticulum Stress

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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

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Principal Investigators:
(in alphabetical order) 		Ratna K Vadlamudi, Ph.D., UT Health San Antonio, United States
Submitting User: stweintraub
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