Inhibition of NOTCH Signaling by Gamma Secretase Inhibitor Engages the RB Pathway and Elicits Cell Cycle Exit in T-Cell Acute Lymphoblastic Leukemia Cells

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 7; pp. 3060 - 3068
• Main Authors: RAO, Sudhir S, O'NEIL, Jennifer, VAN DER PLOEG, Lex H. T, CARROLL, Pamela M, DRAETTA, Giulio F, LOOK, A. Thomas, STACK, Peter R, WINTER, Christopher G, LIBERATOR, Cole D, HARDWICK, James S, XUDONG DAI, ZHANG, Theresa, TYMINSKI, Edyta, JING YUAN, KOHL, Nancy E, RICHON, Victoria M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-04-2009
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cyclic S-Oxides - pharmacology; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p19 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p27; G1 Phase - drug effects; G1 Phase - genetics; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Pharmacology. Drug treatments; Phosphorylation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protease Inhibitors - pharmacology; Receptor, Notch1 - antagonists & inhibitors; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Retinoblastoma Protein - metabolism; S Phase - drug effects; S Phase - genetics; Signal Transduction - drug effects; Thiadiazoles - pharmacology; Transcription, Genetic; Transfection; Tumors; Rb protein; Signal transduction; Notch receptor; Retinoblastoma gene; Cell cycle; γ Secretase inhibitor; Inhibition; Cell; In vitro; Cell signaling; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-4295

NOTCH signaling is deregulated in the majority of T-cell acute lymphoblastic leukemias (T-ALL) as a result of activating mutations in NOTCH1. Gamma secretase inhibitors (GSI) block proteolytic activation of NOTCH receptors and may provide a targeted therapy for T-ALL. We have investigated the mechanisms of GSI sensitivity across a panel of T-ALL cell lines, yielding an approach for patient stratification based on pathway activity and also providing a rational combination strategy for enhanced response to GSI. Whereas the NOTCH1 mutation status does not serve as a predictor of GSI sensitivity, a gene expression signature of NOTCH pathway activity does correlate with response, and may be useful in the selection of patients more likely to respond to GSI. Furthermore, inhibition of the NOTCH pathway activity signature correlates with the induction of the cyclin-dependent kinase inhibitors CDKN2D (p19(INK4d)) and CDKN1B (p27(Kip1)), leading to derepression of RB and subsequent exit from the cell cycle. Consistent with this evidence of cell cycle exit, short-term exposure of GSI resulted in sustained molecular and phenotypic effects after withdrawal of the compound. Combination treatment with GSI and a small molecule inhibitor of CDK4 produced synergistic growth inhibition, providing evidence that GSI engagement of the CDK4/RB pathway is an important mechanism of GSI action and supports further investigation of this combination for improved efficacy in treating T-ALL.