GSE168800
Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress
Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death. Overall design: MDA-MB-231 and BT-549 cells were cultured in RPMI1640 (Gibco) supplemented with 10% FBS, 0.2% Normocin and 1% penicillin-streptomycin. SUM-159 cells were cultured in F-12 (Gibco) supplemented with 10% FBS, 0.2% Normocin and 1% penicillin-streptomycin. Cells were treated with DMSO or ERX-41. For mRNAseq samples, ERX-41 treated cells were treated with 1 uM of ERX-41 for 2 or 4 hours. For CRISPR screen samples, ERX-41 treated cells were treated with 0.25 uM (1st screen) or 0.5 uM (2nd screen) for 3 weeks.