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

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 3

MALT1 inhibition by MI-2 decreases MALT1 paracaspase activity and suppresses proliferation in MCL cells.

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MALT1 inhibition by MI-2 decreases MALT1 paracaspase activity and suppre...
(A) Endogenous MALT1 cleavage activity detected in JeKo-1 cells and JeKo BTK KD-2 cells upon MALT1 inhibition by MI-2 at the indicated concentrations and treatment times. Each treatment for the indicated cell lines was set up in triplicate. Statistical significance was determined based on the F test of the slope from the linear regression model and multiple comparison was adjusted using Šídák’s approach. (B) MALT1 inhibitor MI-2 potently inhibited viability in JeKo-1, JeKo-R, and JeKo BTK KD-1 and -2 cells. (C) MI-2 effectively inhibited viability in JeKo-1 cells and JeKo BTK KD-2 cells, but not their counterparts with stable MALT1 KD. Error bars were generated from at least 3 independent replicates (B and C). (D) MI-2 induced cleavage (CL) of full-length PARP (PARP_FL) and caspase 3 in JeKo BTK KD-2 cells and primary patient cells. (E and F) NSG mice bearing luciferase-expressing JeKo BTK KD-2–derived subcutaneous xenografts were treated with vehicle (n = 5) or MI-2 (n = 5) at 25 mg/kg daily via intraperitoneal injection for 24 days. Tumor growth was monitored by live animal luminescence imaging (E) and the luciferase flux was plotted (F). Two-way ANOVA was used in C and F, and statistical significance was determined based on the adjusted P values using Šídák’s method. *P < 0.05; ***P < 0.001; ****P < 0.0001.