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

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. Overall design: We conducted RNA sequencing analysis on subcutaneous T-cell lymphoma tumors derived from T-cell lymphoma xenografts that had undergone 1 week treatment with either a ZAP-70 inhibitor candidate (2 candidates tested), as well as the vehicle group receiving the vehicle treatment(n=6/group).