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

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

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. vadlamudi@uthscsa.edu.
  • 13 CDP program, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. vadlamudi@uthscsa.edu.
  • 14 Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, USA. vadlamudi@uthscsa.edu.
  • 15 Department of Chemistry and Biochemistry, University of Texas at Dallas, Richardson, TX, USA. jungmo.ahn@utdallas.edu.
  • 16 Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Ganesh.Raj@utsouthwestern.edu.
  • 17 Simmons Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Ganesh.Raj@utsouthwestern.edu.
  • 18 Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. Ganesh.Raj@utsouthwestern.edu.
PMID: 35654861 DOI: 10.1038/s43018-022-00389-8
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.

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