Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition
Menée à l'aide de lignées cellulaires de leucémie lymphoblastique aiguë à lymphocytes T et à l'aide de xénogreffes sur des modèles murins, cette étude met en évidence l'efficacité et la sécurité d'une stratégie thérapeutique consistant à inhiber la préséniline-1, un composant d'une gamma-sécrétase impliquée dans l'activation du récepteur transmembranaire NOTCH
The NOTCH signaling pathway is frequently mutated in T cell acute lymphoblastic leukemia and therefore presents a potential therapeutic target. Previous researchers tried to inhibit γ-secretase, a protease that cleaves NOTCH and thereby activates it. Unfortunately, nonspecific inhibition of γ-secretase proved to be too toxic for clinical use because of on-target side effects in a variety of healthy tissues. Habets et al. found that presenilin-1, a component of some γ-secretase complexes, is highly expressed in T cell leukemia relative to healthy T cells. The authors then demonstrated that targeting presenilin-1 is effective and safe in mouse models, suggesting this strategy’s potential for translation.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.