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Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Xihui LiuSuryavathi ViswanadhapalliShourya KumarTae-Kyung LeeAndrew MooreShihong MaLiping ChenMichael HsiehMengxing LiGangadhara R SareddyKarla ParraEliot B BlattTanner C ReeseYuting ZhaoAnnabel ChangHui YanZhenming XuUday P PratapZexuan LiuCarlos M RoggeroZhenqiu TanSusan T WeintraubYan PengRajeshwar R TekmalCarlos L ArteagaJennifer Lippincott-SchwartzRatna K VadlamudiJung-Mo AhnGanesh V Raj
Published in: Nature cancer (2022)
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.
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