2. Academic Validation
  3. A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

A Unified Approach to Targeting the Lysosome's Degradative and Growth Signaling Roles

  • Cancer Discov. 2017 Nov;7(11):1266-1283. doi: 10.1158/2159-8290.CD-17-0741.
Vito W Rebecca 1,  Michael C Nicastri 2,  Noel McLaughlin 2,  Colin Fennelly 1,  Quentin McAfee 1,  Amruta Ronghe 3,  Michel Nofal 4,  Chun-Yan Lim 5,  Eric Witze 6,  Cynthia I Chude 1,  Gao Zhang 3,  Gretchen M Alicea 3,  Shengfu Piao 1,  Sengottuvelan Murugan 1,  Rani Ojha 1,  Samuel M Levi 2,  Zhi Wei 7,  Julie S Barber-Rotenberg 8,  Maureen E Murphy 3,  Gordon B Mills 9,  Yiling Lu 9,  Joshua Rabinowitz 4,  Ronen Marmorstein 8,  Qin Liu 3,  Shujing Liu 10,  Xiaowei Xu 10,  Meenhard Herlyn 3,  Roberto Zoncu 5,  Donita C Brady 6,  David W Speicher 3,  Jeffrey D Winkler 11 12,  Ravi K Amaravadi 13 12
Affiliations

Affiliations

  • 1 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 2 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 3 Molecular and Cellular Oncogenesis Program and Melanoma Research Center, Wistar Institute, Philadelphia, Pennsylvania.
  • 4 Department of Chemistry and Integrative Genomics, Princeton University, Princeton, New Jersey.
  • 5 Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California.
  • 6 Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 7 Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey.
  • 8 Department of Biochemistry and Biophysics, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 9 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 10 Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 11 Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania. ravi.amaravadi@uphs.upenn.edu winkler@sas.upenn.edu.
  • 12 Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
  • 13 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. ravi.amaravadi@uphs.upenn.edu winkler@sas.upenn.edu.
PMID: 28899863 DOI: 10.1158/2159-8290.CD-17-0741
Abstract

Lysosomes serve dual roles in Cancer metabolism, executing catabolic programs (i.e., Autophagy and macropinocytosis) while promoting mTORC1-dependent anabolism. Antimalarial compounds such as chloroquine or quinacrine have been used as lysosomal inhibitors, but fail to inhibit mTOR signaling. Further, the molecular target of these agents has not been identified. We report a screen of novel dimeric antimalarials that identifies dimeric quinacrines (DQ) as potent Anticancer compounds, which concurrently inhibit mTOR and Autophagy. Central nitrogen methylation of the DQ linker enhances lysosomal localization and potency. An in situ photoaffinity pulldown identified palmitoyl-protein thioesterase 1 (PPT1) as the molecular target of DQ661. PPT1 inhibition concurrently impairs mTOR and lysosomal catabolism through the rapid accumulation of palmitoylated proteins. DQ661 inhibits the in vivo tumor growth of melanoma, pancreatic Cancer, and colorectal Cancer mouse models and can be safely combined with chemotherapy. Thus, lysosome-directed PPT1 inhibitors represent a new approach to concurrently targeting mTORC1 and lysosomal catabolism in Cancer.Significance: This study identifies chemical features of dimeric compounds that increase their lysosomal specificity, and a new molecular target for these compounds, reclassifying these compounds as targeted therapies. Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting Autophagy, thereby providing a new strategy for Cancer therapy. Cancer Discov; 7(11); 1266-83. ©2017 AACR.See related commentary by Towers and Thorburn, p. 1218This article is highlighted in the In This Issue feature, p. 1201.

Figures
Products