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

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 1

MALT1 is overexpressed in ibrutinib-resistant MCL cell lines and primary MCL cells.

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MALT1 is overexpressed in ibrutinib-resistant MCL cell lines and primary...
(A) Heatmap with MALT1 highlighted in the right as one of the top DEGs in IBN-R MCL cells compared with IBN-S cells. (B) Volcano plot shows MALT1 was upregulated in the IBN-R group. (C) MALT1 mRNA expression in IBN-R versus IBN-S and Dual-R versus Dual-S groups. (D) Violin plot shows MALT1 mRNA expression in IBN-R (n = 17) versus IBN-S (n = 4) MCL cells at single-cell resolution determined by single-cell RNA sequencing. Statistical significance was calculated using Wilcoxon’s rank-sum test. (E) MALT1 mRNA expression determined by qPCR in IBN-R (n = 9), Dual-R (n = 4), and IBN-S (n = 13) cells. Statistical significance was determined based on the adjusted P values using Dunnett’s approach. **P < 0.01; ***P < 0.001. (F) High MALT1 mRNA expression correlated with progress-free survival in MCL patients. The log-rank test was used to assess the statistical significance of progression-free survival. (G) GSEA identifies NF-κB signaling pathways as top cancer hallmarks that were upregulated in IBN-R cells compared with IBN-S cells. FDRs were generated using the Benjamini-Hochberg method. Box-and-whisker plots in C and E show the median ± 1 quartile, with whiskers extending from the hinge to the smallest and largest values within 1.5 × (interquartile range) from the box boundaries. The values beyond the ends of the whiskers are outliers. All other data represent the mean ± SD.