1. Academic Validation
  2. Targeting UGCG overcomes resistance to lysosomal autophagy inhibition

Targeting UGCG overcomes resistance to lysosomal autophagy inhibition

  • Cancer Discov. 2022 Nov 4;CD-22-0535. doi: 10.1158/2159-8290.CD-22-0535.
Vaibhav Jain 1 Sandra L Harper 2 Amanda M Versace 3 Dylan Fingerman 4 Gregory Schuyler Brown 2 Monika Bhardwaj 3 Mary Ann S Crissey 5 Aaron R Goldman 2 Gordon Ruthel 6 Qin Liu 4 Aleksandra Zivkovic 7 Holger Stark 8 Meenhard Herlyn 2 Phyllis A Gimotty 5 David W Speicher 2 Ravi K Amaravadi 9
Affiliations

Affiliations

  • 1 University of Pennsylvania, Philadelphia, United States.
  • 2 The Wistar Institute, Philadelphia, PA, United States.
  • 3 University of Pennsylvania, Philadelphia, Pennsylvania, United States.
  • 4 The Wistar Institute, Philadelphia, United States.
  • 5 University of Pennsylvania, Philadelphia, PA, United States.
  • 6 UPENN, Philadelphia, Pennsylvania, United States.
  • 7 Heinrich Heine University Düsseldorf, Duesseldorf, Germany.
  • 8 Heinrich Heine University Düsseldorf, Düsseldorf, NRW, Germany.
  • 9 Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
Abstract

Lysosomal Autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance Cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple Cancer cell lines. Lipidomics showed that LAI increased Cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. While UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new Cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted.

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