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

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 (DQs) 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, 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.

Targeting the Lysosome for Cancer Therapy

“…al. (8) extend a previous study from the same labs (9) that reported that dimerization of chloroquine could increase its potency as an autophagy inhibitor by more systematically testing dimerized antimalarials. Dimerization of the oldest antimalarial drug, quinacrine, was particularly potent at suppressing tumor growth and the authors went on to optimize the linker sequence.…”

“…For example, it has been known for many years that chloroquine can bind to DNA (7). A new paper from the laboratories of Ravi Amaravadi and Jeffrey Winkler (8) takes a systematic approach to lysosome inhibition and, for the first time, describes an agent that can inhibit multiple cancer-driving functions of the lysosome.…”

Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

“…Overall, functional inhibition of autophagy with CQ enhanced olaparib's activity in cell cultures in 6 ovarian cancer cell lines. Quinacrine dimers have recently been developed that have 1000-fold greater potency than HCQ, 13 and they could facilitate clinical trials of PARP inhibitors with inhibitors of autophagy. Importantly, activation of autophagy was detected within the therapeutic plasma concentration (C max ; 5 µM) of olaparib.…”

Autophagy and mitochondrial metabolism: insights into their role and therapeutic potential in chronic myeloid leukaemia

“…Interestingly, Rebecca et al . recently identified palmitoyl‐protein thioesterase 1 (PPT1), as a molecular target for dimeric quinacrines, which are more potent analogues of HCQ and Lys05 . Strikingly, the action of these compounds is dual; inactivates mTORC1 by disrupting its lysosomal localization and deacidifies the lysosomes, which leads to a block in the autophagic flux.…”