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

被引：26

作者：

Jiang, Vivian Changying ^{[1
]}

Liu, Yang ^{[1
]}

Lian, Junwei ^{[1
]}

Huang, Shengjian ^{[1
]}

Jordan, Alexa ^{[1
]}

Cai, Qingsong ^{[1
]}

Lin, Ruitao ^{[2
]}

Yan, Fangfang ^{[3
]}

McIntosh, Joseph ^{[1
]}

Li, Yijing ^{[1
]}

Che, Yuxuan ^{[1
]}

Chen, Zhihong ^{[1
]}

Vargas, Jovanny ^{[1
]}

Badillo, Maria ^{[1
]}

Bigcal, John Nelson ^{[1
]}

Lee, Heng-Huan ^{[1
]}

Wang, Wei ^{[1
]}

Yao, Yixin ^{[1
]}

Nie, Lei ^{[1
]}

Flowers, Christopher R. ^{[1
]}

Wang, Michael ^{[1
,4
,5
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA

[3] Univ Texas Hlth Sci Ctr Houston, Ctr Precis Hlth, Sch Biomed Informat, Houston, TX USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cellular Therapy, Houston, TX USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, Houston, TX 77030 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 03期

关键词：

KAPPA-B; PARACASPASE MALT1; RISK-STRATIFICATION; IN-VITRO; ACTIVATION; EXPRESSION; IBRUTINIB; CLEAVAGE; CARMA1; LYMPHOCYTOSIS;

D O I：

10.1172/JCI165694

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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-KB, 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.

引用

页数：15

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