Language

English

Publication Date

3-10-2023

Journal

Research Square

DOI

10.21203/rs.3.rs-2653461/v1

PMID

36945511

PMCID

PMC10029087

PubMedCentral® Posted Date

3-10-2023

PubMedCentral® Full Text Version

Pre-Print

Abstract

Mantle cell lymphoma (MCL) is a heterogeneous disease with a poor prognosis. Despite years of research in MCL, relapse occurs in patients with current therapeutic options necessitating the development of novel therapeutic agents. Previous attempts to pharmacologically inhibit SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas, and previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin’s lymphoma patients. This suggests that SRC-3 may play a role in the progression of B cell lymphoma and that the development of selective SRC inhibitors should be investigated. This study aimed to investigate novel SRC-3 inhibitors, SI-10 and SI-12, in mantle cell lymphoma. The cytotoxic effects of SI-10 and SI-12 were evaluated in a panel of MCL cell lines in vitro by resazurin assay. The in vivo efficacy of SI-10 was confirmed in two ibrutinib-resistant models: an immunocompetent disseminated A20 mouse model of B-cell lymphoma and a human PDX model of MCL. SI-10 treatment resulted in dose-dependent cytotoxicity in a panel of MCL cell lines in vitro. Notably, SI-10 treatment also resulted in a significant extension of survival in vivo with low toxicity in both ibrutinib-resistant murine models. We have investigated SI-10 as a novel anti-lymphoma compound via the inhibition of SRC-3 activity. These findings indicate that targeting SRC-3 should be investigated in combination with current clinical therapeutics as a novel strategy to expand the therapeutic index and to improve lymphoma outcomes.

Keywords

Mantle cell lymphoma, SRC-3, drug resistance, antitumor activity

Published Open-Access

yes

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