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Impact of ZAP-70 kinase inhibitors on gene expression in murine xenograft models of malignant T-cell lymphoma

ABSTRACT: T-cell lymphoma (TCL) is a group of lymphomas derived from mature T and NK cells, often characterized by an aggressive clinical course with limited effective treatments available. Emerging evidence underscores the pivotal role of T cell receptor signaling (TCR) in the pathobiology of T cell lymphomas. ZAP-70, a protein tyrosine kinase belonging to the Syk / ZAP-70 family, is expressed in T lymphocytes and in NK cells and is an essential kinase in the proximal signaling of the TCR. The main objective of this project is to study the therapeutic potential of blocking TCR signaling by specific inhibition of the ZAP-70 protein. For this, we have developed two ZAP-70 kinase inhibitory molecules and have analyzed their antitumor efficacy in T-cell lymphoma xenografts. All this would emulate what has been observed in B-cell lymphomas, where signaling through the B-cell receptor is crucial for the survival and growth of tumor cells and blocking this pathway is of enormous therapeutic efficacy. Based on the results of the research proposed here, we will be able to establish the basis for further early phase clinical trials.

ORGANISM(S): Homo sapiens

PROVIDER: GSE243897 | GEO | 2023/09/28

REPOSITORIES: GEO

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Project description:Mukhopadhyay2013 - T cell receptor proximal signaling reveals emergent ultrasensitivity This model is described in the article: Systems model of T cell receptor proximal signaling reveals emergent ultrasensitivity. Mukhopadhyay H, Cordoba SP, Maini PK, van der Merwe PA, Dushek O. PLoS Comput. Biol. 2013; 9(3): e1003004 Abstract: Receptor phosphorylation is thought to be tightly regulated because phosphorylated receptors initiate signaling cascades leading to cellular activation. The T cell antigen receptor (TCR) on the surface of T cells is phosphorylated by the kinase Lck and dephosphorylated by the phosphatase CD45 on multiple immunoreceptor tyrosine-based activation motifs (ITAMs). Intriguingly, Lck sequentially phosphorylates ITAMs and ZAP-70, a cytosolic kinase, binds to phosphorylated ITAMs with differential affinities. The purpose of multiple ITAMs, their sequential phosphorylation, and the differential ZAP-70 affinities are unknown. Here, we use a systems model to show that this signaling architecture produces emergent ultrasensitivity resulting in switch-like responses at the scale of individual TCRs. Importantly, this switch-like response is an emergent property, so that removal of multiple ITAMs, sequential phosphorylation, or differential affinities abolishes the switch. We propose that highly regulated TCR phosphorylation is achieved by an emergent switch-like response and use the systems model to design novel chimeric antigen receptors for therapy. This model is hosted on BioModels Database and identified by: MODEL1604100000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Impact of ZAP-70 kinase inhibitors on gene expression in murine xenograft models of malignant T-cell lymphoma

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