A unified approach to targeting the lysosome’s degradative and growth signaling roles

Vito W. Rebecca, Michael C. Nicastri, Noel McLaughlin, Colin Fennelly, Quentin McAfee, Amruta Ronghe, Michel Nofal, Chun Yan Lim, Eric Witze, Cynthia I. Chude, Gao Zhang, Gretchen M. Alicea, Shengfu Piao, Sengottuvelan Murugan, Rani Ojha, Samuel M. Levi, Zhi Wei, Julie S. Barber-Rotenberg, Maureen E. Murphy, Gordon B. MillsYiling Lu, Joshua Rabinowitz, Ronen Marmorstein, Qin Liu, Shujing Liu, Xiaowei Xu, Meenhard Herlyn, Roberto Zoncu, Donita C. Brady, David W. Speicher, Jeffrey D. Winkler, Ravi K. Amaravadi

Research output: Contribution to journalArticlepeer-review

146 Scopus citations


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 photoaffin-ity 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.

Original languageEnglish (US)
Pages (from-to)1266-1283
Number of pages18
JournalCancer Discovery
Issue number11
StatePublished - Nov 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology


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