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. 2021 Feb;26(2):e298-e305.
doi: 10.1002/onco.13595. Epub 2020 Nov 26.

More Insights on the Use of γ-Secretase Inhibitors in Cancer Treatment

Pilar López-Nieva #  1   2   3 , Laura González-Sánchez #  1   2   3 , María Ángeles Cobos-Fernández  1   2 , Raúl Córdoba  2 , Javier Santos  1   2   3 , José Fernández-Piqueras  1   2   3
Affiliations

More Insights on the Use of γ-Secretase Inhibitors in Cancer Treatment

Pilar López-Nieva et al. Oncologist. 2021 Feb.

Abstract

The NOTCH1 gene encodes a transmembrane receptor protein with activating mutations observed in many T-cell acute lymphoblastic leukemias (T-ALLs) and lymphomas, as well as in other tumor types, which has led to interest in inhibiting NOTCH1 signaling as a therapeutic target in cancer. Several classes of Notch inhibitors have been developed, including monoclonal antibodies against NOTCH receptors or ligands, decoys, blocking peptides, and γ-secretase inhibitors (GSIs). GSIs block a critical proteolytic step in NOTCH activation and are the most widely studied. Current treatments with GSIs have not successfully passed clinical trials because of side effects that limit the maximum tolerable dose. Multiple γ-secretase-cleavage substrates may be involved in carcinogenesis, indicating that there may be other targets for GSIs. Resistance mechanisms may include PTEN inactivation, mutations involving FBXW7, or constitutive MYC expression conferring independence from NOTCH1 inactivation. Recent studies have suggested that selective targeting γ-secretase may offer an improved efficacy and toxicity profile over the effects caused by broad-spectrum GSIs. Understanding the mechanism of GSI-induced cell death and the ability to accurately identify patients based on the activity of the pathway will improve the response to GSI and support further investigation of such compounds for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL. IMPLICATIONS FOR PRACTICE: γ-secretase has been proposed as a therapeutic target in numerous human conditions, including cancer. A better understanding of the structure and function of the γ-secretase inhibitor (GSI) would help to develop safe and effective γ-secretase-based therapies. The ability to accurately identify patients based on the activity of the pathway could improve the response to GSI therapy for the treatment of cancer. Toward these ends, this study focused on γ-secretase inhibitors as a potential therapeutic target for the design of anti-NOTCH1 therapies for the treatment of T-cell acute lymphoblastic leukemias and lymphomas.

Keywords: Broad-spectrum γ-secretase inhibitors; MYC gene dosage; New resistance factor; PF-03084014 treatment; Selective γ-secretase inhibitors; T-cell lymphoblastic cell lines.

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Conflict of interest statement

Disclosures of potential conflicts of interest may be found at the end of this article.

Figures

Figure 1
Figure 1
Notch signaling pathway and clinical trials with γ‐secretase inhibitors. (A): Schematic representation of Notch signaling pathway. Signaling is initiated by the interaction of Notch with Delta‐like ligands or Jagged ligands on the surface of instructing cells. Then two sequential proteolytic cleavages occur, the first mediated by an ADAM family protease (S2 cleavage) and the next by a γ‐secretase complex (S3 cleavage), resulting in the release of NICDs. NICDs are translocated to the nucleus and bind with transcriptional regulators to activate the expression of Notch downstream targets. The downstream proteins promote cell proliferation, inhibit cell apoptosis, and maintain cancer stem‐like phenotypes. (B): Clinical trials. A summary of the clinical trials with results employing γ‐secretase inhibitors in the treatment of cancer (https://clinicaltrials.gov). Abbreviations: ADAM, a disintegrin and metalloproteinase; CSL, C promoter‐binding factor; DLL3, Delta‐like ligand 3; HAT, histone acetyltransferase; mAb, monoclonal antibody; MAML‐1, Mastermind‐like 1; NICD, Notch intracellular domain; SKIP, ski‐interacting protein; TACE, TNF‐α–converting enzyme.
Figure 2
Figure 2
MYC gene dosage and γ‐secretase inhibitors. (A): Microarray‐based comparative genomic hybridization analysis (aCGH) of chromosome 8 to screen for copy number alterations of MYC in HPB‐ALL, SUP‐T1, and MOLT‐4 cell lines. The aCGH plots of chromosome 8 show alterations outside the thresholds of +0.5 for gain and −0.5 for loss, as well as borderline alterations at the +0.5 threshold. (B): Representative FISH signal patterns using the Myc break‐apart and DAKO Y5410 probe in T‐cell acute lymphoblastic leukemia (T‐ALL) cell lines. Interphase FISH analyses in at least 200 nuclei were evaluated. The colocalization of red and green signals excludes the presence of a translocation affecting the MYC. In the HPB‐ALL image, there are >50% of nuclei with two signals both for MYC. This case has a normal disomic status. In the other two images (SUP‐T1 and MOLT‐4) there are >50% of nuclei with five signals for MYC. These cases are representative of a gain for chromosome 8. (C–E): Effects of treatment of HPB‐ALL, SUP‐T1, and MOLT‐4 cells lines with γ‐secretase inhibitor (GSI) PF‐03084014 (0, 0.1, 1, and 10 μM) for 72 hours. (C): GSI PF‐03084014 treatment in T‐ALL cells inhibits Notch and induces apoptosis. Western blotting for detection of 120‐kDa NICD and MYC. (D): MYC mRNA expression is downregulated by PF‐03084014 in HPB‐ALL cell line. Real‐time polymerase chain reaction was performed for mRNAs expression levels of MYC (n = 3). The expression of specific mRNA is relative to housekeeping genes and was normalized to that the same ratio in unstimulated cells. (E): Flow cytometry analysis of PF‐03084014–treated cells (0–10 μM) stained with PI. Cell death was quantified by staining with propidium iodide using flow cytometry; treatment with PF‐03084014 dramatically increased the number of HPB‐ALL PI‐positive cells (n = 3). Each line shows the normalized data of stained cells percentage. Data are expressed as means ± SD. Significant differences using Student's t test (*p < .05, **p < .01, ***p < .001). Data normalized to vehicle treated cells (0 μM). Abbreviations: FISH, fluorescence in situ hybridization; NICD, Notch intracellular domain; PI, propidium iodide.
Figure 3
Figure 3
Omics‐based tests, including genomic tests, mRNA in situ hybridization, and immunohistochemical (among others) analyses, should be integrated to construct a Notch‐related knowledge base for the optimization of Notch‐targeted therapy. Synergistic combinations of NOTCH inhibition and chemotherapy should be considered. Templates to build this figure were obtained from SMART Servier Medical Art (Attribution 3.0 Unported, CC BY 3.0). Abbreviations: DLL3, Delta‐like ligand 3; mAb, monoclonal antibody.
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