Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 02, 2022
- Source ID
- 10.1038/s43018-022-00389-8
Entities
People
- Andrew Moore
- Annabel Chang
- Carlos L Arteaga
- Carlos M. Roggero
- Eliot B. Blatt
- Ganesh V Raj
- Gangadhara R Sareddy
- Hui Yan
- Jennifer Lippincott-Schwartz
- Jung-Mo Ahn
- Karla Parra
- Liping Chen
- Mengxing Li
- Michael Hsieh
- Peng Yan
- Rajeshwar R. Tekmal
- Ratna K Vadlamudi
- Shihong Ma
- Shourya Kumar
- Suryavathi Viswanadhapalli
- Susan T. Weintraub
- Tae-kyung Lee
- Tanner C. Reese
- Uday P. Pratap
- Xihui Liu
- Yuting Zhao
- Zexuan Liu
- Zhenming Xu
- Zhenqiu Tan
Organizations
- Cancer Prevention and Research Institute of Texas
- National Cancer Institute
- Robert A. Welch Foundation
- United States Department of Defense