New research reveals that single-molecule BTK-MALT1 fusion inhibitors are a potential therapeutic strategy for relapsed or refractory (R/R) mantle cell lymphoma (MCL). These first-in-class agents “demonstrate superior efficacy, overcome resistance mechanisms, and hold strong potential to improve clinical outcomes in aggressive B-cell lymphomas,” according to the authors, who presented at the 67th American Society of Hematology Annual Meeting and Exposition.
MCL, an aggressive B-cell malignancy, is associated with poor outcomes when the disease relapses or becomes refractory. Progression occurs when the B-cell receptor (BCR) signaling pathway is activated, and Bruton’s tyrosine kinase (BTK) is a critical component of this pathway. BTK inhibitors (BTKis) have been shown to be effective against the disease, but some patients develop resistance to BTKis. Current research is exploring MALT1.
Research is exploring a novel class of bifunctional molecules that simultaneously target BTK and MALT1 (mucosa-associated lymphoid tissue lymphoma translocation protein 1), a key regulator of immune signaling pathways. Previous studies have tested this combination approach in established MCL cell lines, patient samples, and organoid systems. For the current study, Vivian Jiang of the University of Texas MD Anderson Cancer Center in Houston and colleagues aimed to identify compounds with the highest potential. They assessed cell viability, cell-cycle progression, apoptosis, transcriptomic changes, epithelial-mesenchymal transition (EMT), metastasis-related gene expression, and tumor invasiveness.
The researchers found that MZ0150-1 had potent anti-tumor activity, inducing cell-cycle arrest and apoptosis and impairing tumor migration and invasiveness. The compound was well tolerated in peripheral blood mononuclear cells from healthy donors, indicating it may have a good safety profile. However, it was associated with increased cytotoxicity compared with pirtobrutinib (a BTKi) and safimaltib (a MALT1i).
The researchers then synthesized a derivative, MZ0481, to enhance potency. It demonstrated superior efficacy both in vitro and in vivo, with no observed toxicities or adverse events.
The authors concluded that first-in-class BTK-MALT1 fusion inhibitors show promise in overcoming BTKi resistance. The approach demonstrated superior efficacy, safety, and potential to improve outcomes in R/R MCL.
Reference
Jiang V, Zhou M, Kim H, et al. First-in-class dual BTK-MALT1 fusion inhibitors for treating resistant mantle cell lymphoma. Abstract abs25-11874. Presented at: the 67th American Society of Hematology Annual Meeting and Exposition, Dec. 6-9, 2025, Orlando, FL.
