Identification of MALT1 feedback mechanisms enables rational design of potent antilymphoma regimens for ABC-DLBCL

Abstract

MALT1 inhibitors are promising therapeutic agents for B-cell lymphomas that are dependent on constitutive or aberrant signaling pathways. However, a potential limitation for signal transduction–targeted therapies is the occurrence of feedback mechanisms that enable escape from the full impact of such drugs. Here, we used a functional genomics screen in activated B-cell–like (ABC) diffuse large B-cell lymphoma (DLBCL) cells treated with a small molecule irreversible inhibitor of MALT1 to identify genes that might confer resistance or enhance the activity of MALT1 inhibition (MALT1i). We find that loss of B-cell receptor (BCR)- and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity, whereas loss of negative regulators of these pathways (eg, TRAF2, TNFAIP3) promoted resistance. These findings were validated by knockdown of individual genes and a combinatorial drug screen focused on BCR and PI3K pathway–targeting drugs. Among these, the most potent combinatorial effect was observed with PI3Kδ inhibitors against ABC-DLBCLs in vitro and in vivo, but that led to an adaptive increase in phosphorylated S6 and eventual disease progression. Along these lines, MALT1i promoted increased MTORC1 activity and phosphorylation of S6K1-T389 and S6-S235/6, an effect that was only partially blocked by PI3Kδ inhibition in vitro and in vivo. In contrast, simultaneous inhibition of MALT1 and MTORC1 prevented S6 phosphorylation, yielded potent activity against DLBCL cell lines and primary patient specimens, and resulted in more profound tumor regression and significantly improved survival of ABC-DLBCLs in vivo compared with PI3K inhibitors. These findings provide a basis for maximal therapeutic impact of MALT1 inhibitors in the clinic, by disrupting feedback mechanisms that might otherwise limit their efficacy.

Proteomic Landscape of Extracellular Vesicles for Diffuse Large B-Cell Lymphoma Subtyping

“…Moreover, upregulation of BCR pathway components in ABC EVs suggests it to be a potential target for therapy since the loss of B-cell receptor (BCR)-and phosphatidylinositol 3-kinase (PI3K)-activating proteins enhanced sensitivity. By contrast, the loss of negative regulators of these pathways (e.g., TRAF2, TNFAIP3) promoted resistance to MALT1 inhibitors [44]. EVs-containing BCR components are of extreme relevance since immunotherapy options targeting BCR components and auxiliary molecules such as the case of newly CD22 CAR T-cell therapy [45] can function as decoys, leading to disease refractoriness [46].…”

TNF Receptor Associated Factor 2 (TRAF2) Signaling in Cancer

“…Immunohistochemical analyses revealed strong expression of TRAF2 in ABC-like DLBCL with significant association with reduced progression-free survival [ 228 ]. Moreover, functional genetic screens in DLBCL cell lines identified TRAF2 as a factor conferring resistance against mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitor and the cereblon E3 ligase–modulating agent CC-122 [ 229 , 230 ]. One of the somatic mutations in TRAF2 identified in DLBCL results in enhanced TRAF2-dependent classical NFκB activation [ 226 ].…”

Recent Advances in PROTACs for Drug Targeted Protein Research

“…Human mucosa-associated lymphoid tissue protein 1 (MALT1) is a protease and scaffold protein involved in NF-κB signal transduction, which is essential for cell proliferation and survival [ 126 ]. Recent studies have found that MALT1 has therapeutic targeting in ABC-type diffuse large B-cell lymphoma (ABC-DLBCL) [ 127 ]. Studies have shown that inhibiting the MALT1 protein causes autoimmune disease and death in mice.…”