Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress PMID: 35654861

ADC Targets in Oncology

2026-04-10

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

Nat Cancer. 2022 Jul;3(7):866-884. doi: 10.1038/s43018-022-00389-8.

Xihui Liu ¹ , Suryavathi Viswanadhapalli ² ³ , Shourya Kumar ¹ , Tae-Kyung Lee ⁴ , Andrew Moore ⁵ , Shihong Ma ¹ , Liping Chen ¹ , Michael Hsieh ¹ , Mengxing Li ² , Gangadhara R Sareddy ² ³ , Karla Parra ¹ , Eliot B Blatt ¹ , Tanner C Reese ¹ , Yuting Zhao ¹ ⁶ , Annabel Chang ¹ , Hui Yan ⁷ , Zhenming Xu ⁷ , Uday P Pratap ² , Zexuan Liu ² , Carlos M Roggero ¹ , Zhenqiu Tan ⁸ , Susan T Weintraub ⁹ , Yan Peng ¹⁰ ¹¹ , Rajeshwar R Tekmal ² ³ , Carlos L Arteaga ¹¹ , Jennifer Lippincott-Schwartz ⁵ , Ratna K Vadlamudi ¹² ¹³ ¹⁴ , Jung-Mo Ahn ¹⁵ , Ganesh V Raj ¹⁶ ¹⁷ ¹⁸

Affiliations

1. Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
2. Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
3. CDP program, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
4. Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA.
5. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
6. Institute of Future Agriculture, Northwest A&F University, Yangling, China.
7. Department of Microbiology, Immunology and Molecular Genetics, The Joe R & Teresa Lozano Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
8. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, China.
9. Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
10. Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
11. Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
12. Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. [email protected].
13. CDP program, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. [email protected].
14. Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. [email protected].
15. Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA. [email protected].
16. Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. [email protected].
17. Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. [email protected].
18. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. [email protected].

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.