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

• Published in: Molecular cancer therapeutics Vol. 23; no. 7; pp. 949 - 960
• Main Authors: Plotnik, Joshua P, Richardson, Adam E, Yang, Haopeng, Rojas, Estela, Bontcheva, Velitchka, Dowell, Colleen, Parsons, Sydney, Wilson, Ashley, Ravanmehr, Vida, Will, Christine, Jung, Paul, Zhu, Haizhong, Partha, Sarathy Karunan, Panchal, Sanjay C, Mali, Raghuveer Singh, Kohlhapp, Frederick J, McClure, Ryan A, Ramathal, Cyril Y, George, Mariam D, Jhala, Manisha, Elsen, Nathaniel L, Qiu, Wei, Judge, Russell A, Pan, Chin, Mastracchio, Anthony, Henderson, Jared, Meulbroek, Jonathan A, Green, Michael R, Pappano, William N
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research (AACR) 02.07.2024; American Association for Cancer Research
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; BASIC BIOLOGICAL SCIENCES; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cell Line, Tumor; Cell Proliferation - drug effects; Disease Models, Animal; Drug Synergism; Humans; Lymphoma, Large B-Cell, Diffuse - drug therapy; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Mice; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - antagonists & inhibitors; Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein - metabolism; Oncology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Small Molecule Therapeutics; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514; 1538-8514
• DOI: 10.1158/1535-7163.MCT-23-0518

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.