Department of Lymphoma and Myeloma and.
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
J Clin Invest. 2023 Feb 1;133(3):e165694. doi: 10.1172/JCI165694.
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.
布鲁顿酪氨酸激酶 (BTK) 已被证实是套细胞淋巴瘤 (MCL) 的靶点，MCL 是一种侵袭性非霍奇金淋巴瘤亚型。然而，BTK 抑制剂耐药是一个主要的临床挑战。我们在此报告，在伊布替尼耐药的 MCL 细胞中，MALT1 是过度表达的基因之一，而其上游的 CARD11 表达则降低。MALT1 的基因敲除或抑制，无论伊布替尼是否敏感，都会导致 MCL 细胞生长出现明显缺陷。相反，CARD11 敲除细胞仅在伊布替尼敏感的细胞中表现出抗肿瘤作用，这表明 MALT1 过表达可能通过绕过 BTK/CARD11 信号来驱动伊布替尼耐药。此外，BTK 敲低和 MALT1 敲除显著损害了 MCL 肿瘤的迁移和扩散，而 MALT1 的药理学抑制通过抑制 NF-κB、PI3K/AKT/mTOR 和整合素信号通路，降低了 MCL 细胞的活力、黏附和迁移。重要的是，用 safimaltib 靶向 MALT1 联合 pirtobrutinib 靶向 BTK，在伊布替尼耐药的 MCL 细胞系和患者来源的异种移植模型中诱导了强大的抗 MCL 活性。因此，我们得出结论，MALT1 过表达与 MCL 对 BTK 抑制剂的耐药性有关，靶向异常的 MALT1 活性可能是克服 BTK 抑制剂耐药的一种有前途的治疗策略，同时靶向 MALT1 和 BTK 可以提高 MCL 的治疗效果和持久性，并改善患者的预后。
