Inhibition of MALT1 and BCL2 Induces Synergistic Antitumor Activity in Models of B-Cell Lymphoma

Overview

Journal Mol Cancer Ther

Date 2024 Mar 20

PMID 38507740

Authors

Joshua P Plotnik

Adam E Richardson

Haopeng Yang

Estela Rojas

Velitchka Bontcheva

Colleen Dowell

Sydney Parsons

Ashley Wilson

Vida Ravanmehr

Christine Will

Paul Jung

Haizhong Zhu

Sarathy Karunan Partha

Sanjay C Panchal

Raghuveer Singh Mali

Frederick J Kohlhapp

Ryan A McClure

Cyril Y Ramathal

Mariam D George

Manisha Jhala

Nathaniel L Elsen

Wei Qiu

Russell A Judge

Chin Pan

Anthony Mastracchio

Jared Henderson

Jonathan A Meulbroek

Michael R Green

William N Pappano

Affiliations

Soon will be listed here.

Abstract

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 inhibitor, venetoclax, which when combined significantly synergizes to elicit deep and durable responses in preclinical models. This work highlights the potential of ABBV-MALT1 monotherapy and combination with venetoclax as effective treatment options for patients with ABC-DLBCL.

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