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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 2

MALT1 acts as an oncogenic tumor driver in ibrutinib-resistant MCL cells.

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MALT1 acts as an oncogenic tumor driver in ibrutinib-resistant MCL cells...
(A) Expression of MALT1, CARD11, and BCL10, and cleavage (cl) of MALT1 substrates, in JeKo-1 and JeKo-1–derived cell lines. (B) Endogenous MALT1 cleavage activity detected in JeKo-1 and JeKo BTK KD-2 cells. Statistical significance was determined based on the F test of the slope from the linear regression model. (C) Expression of MALT1, CARD11, BCL10, and cleavage of MALT1 substrates in 7 additional MCL cell lines. (D) Expression of MALT1 in JeKo-1 cells and JeKo BTK KD-2 cells, with or without MALT1 or CARD11 KD by shRNA. (E and F) MALT1 KD resulted in cell proliferation inhibition in JeKo-1 (E) and JeKo BTK KD-2 (F) cells. (G) Expression of MALT1, CARD11, and BTK in JeKo-1 and JeKo BTK KD-2 cells with or without MALT1 KO, CARD11 KO, or BTK KD. (H) MALT1 KO or CARD11 KO led to decreased cell proliferation in JeKo-1 cells. (I) MALT1 KO, but not CARD11 KO, led to diminished cell proliferation in JeKo BTK KD-2 cells. (J–N) CDX models were established by subcutaneous injection of 5 × 106 JeKo-1 cells and JeKo BTK KD-2 cells, with or without MALT1 or CARD11 KO (n = 5 per group). Tumor size was monitored weekly (J and K). Serum B2M level (serving as a systematic tumor load indicator) was measured by ELISA (L and M). At the end of experiments, subcutaneous tumors were dissected, weighed, and imaged (N). Two-way ANOVA was used in E and F and H–M to assess the effect of 2 factors (i.e., time and cell line) and 1-way ANOVA was used in N. 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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