Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition
Authors list
Roger A Habets Charles E de Bock Lutgarde Serneels Inge Lodewijckx Delphine Verbeke David Nittner Rajeshwar Narlawar Sofie Demeyer James Dooley Adrian Liston Tom Taghon Jan Cools Bart De StrooperAbstract
Given the high frequency of activating NOTCH1 mutations in T cell acute lymphoblastic leukemia (T-ALL), inhibition of the γ-secretase complex remains an attractive target to prevent ligand-independent release of the cytoplasmic tail and oncogenic NOTCH1 signaling. However, four different γ-secretase complexes exist, and available inhibitors block all complexes equally. As a result, these cause severe "on-target" gastrointestinal tract, skin, and thymus toxicity, limiting their therapeutic application. Here, we demonstrate that genetic deletion or pharmacologic inhibition of the presenilin-1 (PSEN1) subclass of γ-secretase complexes is highly effective in decreasing leukemia while avoiding dose-limiting toxicities. Clinically, T-ALL samples were found to selectively express only PSEN1-containing γ-secretase complexes. The conditional knockout of Psen1 in developing T cells attenuated the development of a mutant NOTCH1-driven leukemia in mice in vivo but did not abrogate normal T cell development. Treatment of T-ALL cell lines with the selective PSEN1 inhibitor MRK-560 effectively decreased mutant NOTCH1 processing and led to cell cycle arrest. These observations were extended to T-ALL patient-derived xenografts in vivo, demonstrating that MRK-560 treatment decreases leukemia burden and increased overall survival without any associated gut toxicity. Therefore, PSEN1-selective compounds provide a potential therapeutic strategy for safe and effective targeting of T-ALL and possibly also for other diseases in which NOTCH signaling plays a role.
Journal details
Journal Science Translational Medicine
Volume 11
Issue number 494
Pages eaau6246
Available online
Publication date
Full text links
Publisher website (DOI) 10.1126/scitranslmed.aau6246
Europe PubMed Central 31142678
Pubmed 31142678
Keywords
Type of publication