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 5

MALT1, but not CARD11, is critical for MCL cell dissemination to mouse spleen, liver, and BM.

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MALT1, but not CARD11, is critical for MCL cell dissemination to mouse s...
(A) Schematic illustration of disseminated cell line–derived CDX or PDX models. (B–I) Disseminated CDX models were established using JeKo-1 and JeKo BTK KD-2 cells, with or without MALT1 or CARD11 KO (n = 5 per group). At the end of the experiment, the spleen, liver, BM, and PB were harvested, imaged (F and I), and weighed (D and G) if appropriate. The tumor cell percentages in PB (B), BM (C), spleen (E), and liver (H) were determined by flow cytometry. The CD5+CD20+ cells represent tumor cell populations. (J and K) Freshly isolated primary PDX cells were injected intravenously into NSG mice to establish disseminated PDX models (n = 5 per group). At 6 weeks after injection, the mice were treated with vehicle, ibrutinib (50 mg/kg), or MI-2 (25 mg/kg) daily for 4 weeks. At the end of the experiment, mouse spleens were weighed (J). The CD5+CD20+ MCL cells were measured in spleens (K, left panel), BM (K, middle panel), and PB (K, right panel). One-way ANOVA was used in B–E, H, J, and K, where 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.