Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia

Chang,Yoon Soo; Chang,Yoon Soo; Chang,Yoon Soo; Gills,Joell J.; Gills,Joell J.; Gills,Joell J.; Kawabata,Shigeru; Kawabata,Shigeru; Kawabata,Shigeru; Onozawa,Masahiro; Onozawa,Masahiro; Onozawa,Masahiro; Della Gatta,Giusy; Della Gatta,Giusy; Della Gatta,Giusy; Ferrando,Adolfo A.; Ferrando,Adolfo A.; Ferrando,Adolfo A.; Aplan,Peter D.; Aplan,Peter D.; Aplan,Peter D.; Dennis,Phillip A.; Dennis,Phillip A.; Dennis,Phillip A.

doi:10.3892/ijo.2023.5576

Inhibition of the NOTCH and mTOR pathways by nelfinavir as a novel treatment for T cell acute lymphoblastic leukemia

Authors:
- Yoon Soo Chang
- Joell J. Gills
- Shigeru Kawabata
- Masahiro Onozawa
- Giusy Della Gatta
- Adolfo A. Ferrando
- Peter D. Aplan
- Phillip A. Dennis
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Affiliations: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA, Institute for Cancer Genetics and Joint Centers for Systems Biology, Columbia University, New York, NY 10032, USA
Published online on: October 2, 2023 https://doi.org/10.3892/ijo.2023.5576
Article Number: 128
Copyright: © Chang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

T cell acute lymphoblastic leukemia (T‑ALL), a neoplasm derived from T cell lineage‑committed lymphoblasts, is characterized by genetic alterations that result in activation of oncogenic transcription factors and the NOTCH1 pathway activation. The NOTCH is a transmembrane receptor protein activated by γ‑secretase. γ‑secretase inhibitors (GSIs) are a NOTCH‑targeted therapy for T‑ALL. However, their clinical application has not been successful due to adverse events (primarily gastrointestinal toxicity), limited efficacy, and drug resistance caused by several mechanisms, including activation of the AKT/mTOR pathway. Nelfinavir is an human immunodeficiency virus 1 aspartic protease inhibitor and has been repurposed as an anticancer drug. It acts by inducing endoplasmic reticulum (ER) stress and inhibiting the AKT/mTOR pathway. Thus, it was hypothesized that nelfinavir might inhibit the NOTCH pathway via γ‑secretase inhibition and blockade of aspartic protease presenilin, which would make nelfinavir effective against NOTCH‑associated T‑ALL. The present study assessed the efficacy of nelfinavir against T‑ALL cells and investigated mechanisms of action in vitro and in preclinical treatment studies using a SCL‑LMO1 transgenic mouse model. Nelfinavir blocks presenilin 1 processing and inhibits γ‑secretase activity as well as the NOTCH1 pathway, thus suppressing T‑ALL cell viability. Additionally, microarray analysis of nelfinavir‑treated T‑ALL cells showed that nelfinavir upregulated mRNA levels of CHAC1 (glutathione‑specific γ‑glutamylcyclotransferase 1, a negative regulator of NOTCH) and sestrin 2 (SESN2; a negative regulator of mTOR). As both factors are upregulated by ER stress, this confirmed that nelfinavir induced ER stress in T‑ALL cells. Moreover, nelfinavir suppressed NOTCH1 mRNA expression in microarray analyses. These findings suggest that nelfinavir inhibited the NOTCH1 pathway by downregulating NOTCH1 mRNA expression, upregulating CHAC1 and suppressing γ‑secretase via presenilin 1 inhibition and the mTOR pathway by upregulating SESN2 via ER stress induction. Further, nelfinavir exhibited therapeutic efficacy against T‑ALL in an SCL‑LMO1 transgenic mouse model. Collectively, these findings highlight the potential of nelfinavir as a novel therapeutic candidate for treatment of patients with T‑ALL.

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