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