Resistance to PSEN1-selective γ-secretase inhibitors in T-cell acute lymphoblastic leukemia
Vandersmissen, C.; Demeyer, S.; Jacobs, K.; Boogaerts, L.; Fernandez, S. G.; Segers, H.; Chavez-Gutierrez, L.; Cools, J.
Show abstract
PSEN1-selective gamma-secretase inhibitors (GSI), such as MRK-560, are a potential option for the treatment of T-cell acute lymphoblastic leukemia (T-ALL) with NOTCH1 activating mutations, as these show less toxicity compared to broad-spectrum GSIs. However, an important challenge with targeted therapies for cancer treatment is the rapid development of drug resistance. We therefore investigated if PSEN1 mutations could confer resistance to MRK-560 in T-ALL. We performed a CRISPR-mediated mutagenesis screen in a T-ALL cell line to identify mutations leading to MRK-560 resistance and confirmed these findings in additional cell lines. We identified 3 types of resistance mutations. Mutations at the enzyme-drug interface directly disrupt the interaction of MRK-560 with PSEN1. Mutations at the enzyme-substrate interface cause a shift in relative binding affinities towards drug and/or substrate. The third resistance mechanism involves a mutation at the enzyme-substrate interface that hinders the entrance of MRK-560 to the binding pocket. These findings contribute to the understanding of the PSEN1-selectivity of MRK-560 and can help to design other PSEN1-selective GSIs to overcome resistance in cancer therapy.
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