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Project

PSEN1-selective gamma-secretase inhibition for the treatment of T-cell acute lymphoblastic leukemia (T-ALL)

NOTCH1 gain-of-function mutations are present in the majority of T-ALL cases and mediate enhanced proliferation and survival of the leukemia cells. Importantly, mutant NOTCH1 still requires cleavage by the gamma-secretase complex to become active, making the gamma-secretase complex an important therapeutic target in T-ALL. The Laboratorium for Molecular Biology of Leukemia (Jan Cools) has recently shown that PSEN1-selective gamma-secretase inhibition could be an attractive novel avenue to target T-ALL since this is less toxic than broad-spectrum gamma-secretase inhibition. In this project, we aimed to further investigate the use of PSEN1-selective gamma-secretase inhibitors (GSI) for treatment of T-ALL. We showed that the PSEN1-selective GSI MRK-560 had synergistic effects with dexamethasone in both T-ALL cell lines and PDX mouse models. We further increased survival rates in mice by addition of the XPO1 inhibitor KPT-8602, resulting in the triple combination treatment approach. Importantly, the double or triple combination therapies did not lead to significant weight loss, gastro-intestinal toxicity or macroscopic skin lesions. In a second part, we confirmed that various mutations in human PSEN1 resulted in resistance to MRK-560. We identified mutations at the enzyme-drug interface, which directly disrupt the interaction of MRK-560 with PSEN1. Furthermore, we also found resistance mutations at the enzyme-substrate interface that altered the relative binding affinity for substrate and/or drug. Such mutations conferred resistance to both MRK-560 and broad-spectrum GSIs. 

Date:25 Aug 2020 →  Today
Keywords:Targeted therapy, Leukemia, Signaling, Oncogenes
Disciplines:Cancer therapy
Project type:PhD project