Resistance Mutations in PSEN1 Confer Selective Resistance to the PSEN1-Selective γ-Secretase Inhibitor MRK-560 in T-Cell Acute Lymphoblastic Leukemia

Core Concepts

Mutations in PSEN1, the catalytic subunit of the γ-secretase complex, can confer selective resistance to the PSEN1-selective inhibitor MRK-560 in T-cell acute lymphoblastic leukemia (T-ALL) cells.

Abstract

The authors performed a CRISPR-Cas9 mutagenesis screen in a T-ALL cell line to identify mutations in the PSEN1 gene that could confer resistance to the PSEN1-selective γ-secretase inhibitor MRK-560. They identified three main resistance mechanisms:

1. Mutations at the enzyme-drug interface that directly disrupt the interaction between MRK-560 and PSEN1, such as insertions around amino acids 421-422 and substitutions affecting the intracellular transmembrane domain 6a (amino acids 275-276). These mutations conferred selective resistance to MRK-560 compared to broad-spectrum γ-secretase inhibitors.

2. Mutations at the enzyme-substrate interface that cause a shift in the relative binding affinities towards the drug and/or the substrate (NOTCH1). These mutations, such as 139(M>SL), 164(A>AP), and 165(W>C), resulted in resistance to both MRK-560 and broad-spectrum inhibitors.

3. A mutation at the enzyme-substrate interface, 164(A>AP), that potentially hinders the entrance of MRK-560 to the binding pocket, leading to selective resistance to MRK-560.

The authors validated these resistance mechanisms using mouse embryonic fibroblasts and T-ALL cell lines engineered to express the specific PSEN1 mutations. Their findings provide insights into the PSEN1-selectivity of MRK-560 and can help guide the design of other PSEN1-selective γ-secretase inhibitors to overcome resistance in cancer therapy.

Stats

Mutations in PSEN1 that confer resistance to MRK-560 include:

139(M>SL)
164(A>AP)
165(W>C)
236(V>G) + 237(F>P)
275(A>Y)
275(A>Y) + 276(Q>E)
290_292del(STM)
293(V>R)
298(M>V)
421_422(->A)
421_422(->E)
421_422(->ILS)

Quotes

"Mutations located at the enzyme-drug interface, resulting in selective resistance to the PSEN1-selective GSI, likely interfere directly with the recognition and/or binding of MRK-560."
"Mutations at the enzyme-substrate interface cause a shift in relative binding affinities towards drug and/or substrate."
"The 164(A>AP) mutation potentially hinders the entrance of MRK-560 to the binding pocket, leading to selective resistance to MRK-560."

Key Insights Distilled From

Resistance to PSEN1-selective γ-secretase inhibitors in T-cell acute lymphoblastic leukemia

by Vandersmisse... at www.biorxiv.org 03-06-2024

https://www.biorxiv.org/content/10.1101/2024.03.01.582944v1

Deeper Inquiries

How could the insights from this study be leveraged to design novel PSEN1-selective γ-secretase inhibitors that are less susceptible to resistance mutations

The insights gained from this study can be instrumental in the design of novel PSEN1-selective γ-secretase inhibitors that are less susceptible to resistance mutations. One approach could involve structural modifications to the inhibitors to enhance their binding affinity to PSEN1 while minimizing the impact of mutations that confer resistance. By utilizing the knowledge of the specific amino acid residues in PSEN1 that are critical for inhibitor binding, researchers can tailor the chemical structure of new inhibitors to interact more effectively with the target site. This targeted design strategy can help to overcome the resistance mechanisms identified in the study and improve the efficacy of PSEN1-selective inhibitors in T-ALL treatment.

What other signaling pathways or cellular processes could be targeted to overcome resistance to PSEN1-selective inhibitors in T-ALL

To overcome resistance to PSEN1-selective inhibitors in T-ALL, targeting alternative signaling pathways or cellular processes could be a promising strategy. One potential approach is to explore combination therapies that target multiple nodes in the NOTCH signaling pathway. By simultaneously inhibiting different components of the pathway, such as downstream effectors or feedback mechanisms, it may be possible to circumvent resistance mechanisms that arise from mutations in PSEN1. Additionally, targeting complementary pathways that crosstalk with NOTCH signaling, such as the PI3K-AKT pathway, could provide synergistic effects and enhance the efficacy of PSEN1-selective inhibitors. Furthermore, investigating the tumor microenvironment and immune modulation strategies could offer new avenues to overcome resistance and improve treatment outcomes in T-ALL.

Given the role of PSEN1 in Alzheimer's disease, how might the resistance mechanisms identified in this study inform the development of PSEN1-targeted therapies for neurodegenerative disorders

The resistance mechanisms identified in this study could offer valuable insights for the development of PSEN1-targeted therapies for neurodegenerative disorders, particularly Alzheimer's disease. Understanding how specific mutations in PSEN1 confer resistance to γ-secretase inhibitors in T-ALL can inform the design of novel therapeutic approaches for Alzheimer's disease that are less susceptible to resistance. By incorporating this knowledge into the development of PSEN1-targeted therapies, researchers can optimize the efficacy and specificity of the inhibitors to effectively modulate γ-secretase activity in the context of neurodegenerative disorders. Additionally, exploring the impact of these resistance mechanisms on the processing of amyloid precursor protein and Aβ peptides in Alzheimer's disease could provide new insights into the pathogenesis of the disease and guide the development of more targeted and effective treatments.