Inhibition of Src-3 as a Potential Therapeutic Strategy for Aggressive Mantle Cell Lymphoma

Authors

Imani Bijou
Yang Liu
Dong Lu
Jianwei Chen
Shelby Sloan
Lapo Alinari
David M Lonard
Bert W O'Malley
Michael Wang
Jin Wang

Publication Date

1-1-2024

Journal

PLoS One

DOI

10.1371/journal.pone.0289902

PMID

38683834

PMCID

PMC11057735

PubMedCentral® Posted Date

4-29-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Lymphoma, Mantle-Cell, Animals, Humans, Mice, Cell Line, Tumor, Adenine, Piperidines, Antineoplastic Agents, Pyrimidines, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Pyrazoles, Female

Abstract

Mantle cell lymphoma (MCL) has a poor prognosis and high relapse rates despite current therapies, necessitating novel treatment regimens. Inhibition of SRC-3 show effectiveness in vivo and in vitro in other B cell lymphomas. Additionally, previous studies have shown that SRC-3 is highly expressed in the lymph nodes of B cell non-Hodgkin's lymphoma patients, suggesting SRC-3 may play a role in the progression of B cell lymphoma. 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 vitro and demonstrated dose-dependent cytotoxicity in a panel of MCL cell lines. 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. 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.

Comments

Associated Data