TY - JOUR
T1 - A unified approach to targeting the lysosome’s degradative and growth signaling roles
AU - Rebecca, Vito W.
AU - Nicastri, Michael C.
AU - McLaughlin, Noel
AU - Fennelly, Colin
AU - McAfee, Quentin
AU - Ronghe, Amruta
AU - Nofal, Michel
AU - Lim, Chun Yan
AU - Witze, Eric
AU - Chude, Cynthia I.
AU - Zhang, Gao
AU - Alicea, Gretchen M.
AU - Piao, Shengfu
AU - Murugan, Sengottuvelan
AU - Ojha, Rani
AU - Levi, Samuel M.
AU - Wei, Zhi
AU - Barber-Rotenberg, Julie S.
AU - Murphy, Maureen E.
AU - Mills, Gordon B.
AU - Lu, Yiling
AU - Rabinowitz, Joshua D.
AU - Marmorstein, Ronen
AU - Liu, Qin
AU - Liu, Shujing
AU - Xu, Xiaowei
AU - Herlyn, Meenhard
AU - Zoncu, Roberto
AU - Brady, Donita C.
AU - Speicher, David W.
AU - Winkler, Jeffrey D.
AU - Amaravadi, Ravi K.
N1 - Funding Information:
G.B. Mills reports receiving commercial research grants from Adelson Medical Research Foundation, AstraZeneca, Critical Outcome Technologies, Komen Research Foundation, NanoString, Breast Cancer Research Foundation, Karus, Illumina, Takeda/Millennium Pharmaceuticals, and Pfizer; has received honoraria from the speakers bureaus of Symphogen, MedImmune, AstraZeneca, ISIS Pharmaceuticals, Lilly, Novartis, ImmunoMet, Allostery, Tarveda, and Pfizer; has ownership interest (including patents) in Catena Pharmaceuticals, PTV Ventures, Spindletop Ventures, Myriad Genetics, and ImmunoMet; and is a consultant/advisory board member for Adventist Health, AstraZeneca, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Lilly, Novartis, Tarveda, Tau Therapeutics, Allostery, Catena Pharmaceuticals, Critical Outcome Technologies, ISIS Pharmaceuticals, ImmunoMet, Takeda/Millennium Pharmaceuticals, MedImmune, and Precision Medicine. J.D. Winkler has ownership interest in a patent licensed to Presage and two other unlicensed patents. R.K. Amaravadi has ownership interest (including patents) in Lys05, DQ661, and derivatives, and is a consultant/advisory board member for Presage, Sprint Biosciences, and Immunaccell. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
This work was entirely supported by NIH grants R01CA169134, P01 CA114046, P30 CA016520, SPORE P50 CA174523, 1R01CA198015, CA016672, and P30CA010815.
Publisher Copyright:
© 2017 American Association for Cancer Research.
PY - 2017/11
Y1 - 2017/11
N2 - 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.
AB - 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.
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U2 - 10.1158/2159-8290.CD-17-0741
DO - 10.1158/2159-8290.CD-17-0741
M3 - Article
C2 - 28899863
AN - SCOPUS:85032959641
VL - 7
SP - 1266
EP - 1283
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 11
ER -