Xihui Liu, Suryavathi Viswanadhapalli, Shourya Kumar, Tae-Kyung Lee, Andrew Moore, Shihong Ma, Liping Chen, Michael Hsieh, Mengxing Li, Gangadhara R Sareddy, Karla Parra, Eliot B Blatt, Tanner C Reese, Yuting Zhao, Annabel Chang, Hui Yan, Zhenming Xu, Uday P Pratap, Zexuan Liu, Carlos M Roggero, Zhenqiu Tan, Susan T Weintraub, Yan Peng, Rajeshwar R Tekmal, Carlos L Arteaga, Jennifer Lippincott-Schwartz, Ratna K Vadlamudi, Jung-Mo Ahn, Ganesh V Raj
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...
July 2022: Nature Cancer