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Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma
Vivian Changying Jiang, … , Christopher R. Flowers, Michael Wang
Vivian Changying Jiang, … , Christopher R. Flowers, Michael Wang
Published February 1, 2023
Citation Information: J Clin Invest. 2023;133(3):e165694. https://doi.org/10.1172/JCI165694.
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Research Article Hematology Article has an altmetric score of 33

Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma

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Abstract

Bruton’s tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.

Authors

Vivian Changying Jiang, Yang Liu, Junwei Lian, Shengjian Huang, Alexa Jordan, Qingsong Cai, Ruitao Lin, Fangfang Yan, Joseph McIntosh, Yijing Li, Yuxuan Che, Zhihong Chen, Jovanny Vargas, Maria Badillo, John Nelson Bigcal, Heng-Huan Lee, Wei Wang, Yixin Yao, Lei Nie, Christopher R. Flowers, Michael Wang

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Figure 6

MALT1 inhibition leads to suppressed PI3K/AKT/mTOR signaling, cell adhesion, and migration in vitro.

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MALT1 inhibition leads to suppressed PI3K/AKT/mTOR signaling, cell adhes...
(A) RPPA analysis for MCL cell lines treated with MI-2 at 0, 1, or 2 μM for 6 hours. The heatmap shows the protein expression altered by MI-2 treatment. Each treatment for the indicated cell lines was set up in triplicate. (B) Phosphorylation of AKT, S6, and p90RSK was upregulated in JeKo-R and JeKo BTK KD-1 and -2 cells. (C) The phosphorylation of PLCγ2, BTK, AKT, and ERK was reduced upon MI-2 pretreatment followed by IgM stimulation in JeKo-1 cells. (D) ATP production was suppressed upon MI-2 treatment in MCL cells. Error bars were generated from 3 independent replicates. (E and F) The common DEGs involved in cell adhesion molecules and focal junction downregulated upon MI-2 treatment in both JeKo-1 (E) and JeKo BTK KD-2 (F) cells. Various integrin molecules altered upon MI-2 treatment are also indicated. (G and H) MCL cells were pretreated with DMSO, IBN at 5 μM, or MI-2 at 0.5 μM for 30 minutes and incubated in plates precoated with fibronectin (G) or laminin (H) for 4 hours. The cells adherent to fibronectin or laminin were measured and plotted. (I) MCL cells were pretreated with DMSO, IBN at 5 μM, or MI-2 at 1 μM for 30 minutes, added to Transwell inserts, and incubated in plates preseeded with a monolayer of stromal cells (HS-5) for 6 hours. The MCL cells that passed through the Transwell inserts were measured and plotted. (J) MCL cells were added in Transwell inserts and incubated in plates with preseeded (overnight) monolayers of stromal cells (HS-5) or with only the supernatants harvested from cultured stromal cells (overnight). The MCL cells that passed through the Transwell insert were measured and plotted. Error bars were generated from 3 independent replicates (G–J). Two-way ANOVA was used in D and G–J, and statistical significance was determined based on the adjusted P values using Šídák’s method. Data represent mean ± SD. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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