Proteomics

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


ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Ratna K Vadlamudi, Ph.D.  

PROVIDER: MSV000089091 | MassIVE | Mon Mar 21 16:16:00 GMT 2022

SECONDARY ACCESSION(S): PXD032693

REPOSITORIES: MassIVE

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