Institute of Pathology, University of Würzburg and CCC-Mainfranken, Würzburg, Germany.
Institute of Pathology, University of Duesseldorf, Germany.
Haematologica. 2018 Jan;103(1):116-125. doi: 10.3324/haematol.2017.177162. Epub 2017 Oct 27.
Mantle cell lymphoma and other lymphoma subtypes often spread to the bone marrow, and stromal interactions mediated by focal adhesion kinase frequently enhance survival and drug resistance of the lymphoma cells. To study the role of focal adhesion kinase in mantle cell lymphoma, immunohistochemistry of primary cases and functional analysis of mantle cell lymphoma cell lines and primary mantle cell lymphoma cells co-cultured with bone marrow stromal cells (BMSC) using small molecule inhibitors and RNAi-based focal adhesion kinase silencing was performed. We showed that focal adhesion kinase is highly expressed in bone marrow infiltrates of mantle cell lymphoma and in mantle cell lymphoma cell lines. Stroma-mediated activation of focal adhesion kinase led to activation of multiple kinases (AKT, p42/44 and NF-κB), that are important for prosurvival and proliferation signaling. Interestingly, RNAi-based focal adhesion kinase silencing or inhibition with small molecule inhibitors (FAKi) resulted in blockage of targeted cell invasion and induced apoptosis by inactivation of multiple signaling cascades, including the classic and alternative NF-κB pathway. In addition, the combined treatment of ibrutinib and FAKi was highly synergistic, and ibrutinib resistance of mantle cell lymphoma could be overcome. These data demonstrate that focal adhesion kinase is important for stroma-mediated survival and drug resistance in mantle cell lymphoma, providing indications for a targeted therapeutic strategy.
套细胞淋巴瘤和其他淋巴瘤亚型通常会扩散到骨髓中，而黏着斑激酶介导的基质相互作用常常会增强淋巴瘤细胞的存活和耐药性。为了研究黏着斑激酶在套细胞淋巴瘤中的作用，我们对原发性病例进行了免疫组织化学检测，并使用小分子抑制剂和基于 RNAi 的黏着斑激酶沉默对套细胞淋巴瘤细胞系和与骨髓基质细胞（BMSC）共培养的原发性套细胞淋巴瘤细胞进行了功能分析。结果显示，黏着斑激酶在套细胞淋巴瘤的骨髓浸润物和套细胞淋巴瘤细胞系中高度表达。基质介导的黏着斑激酶激活导致多种激酶（AKT、p42/44 和 NF-κB）的激活，这些激酶对于生存和增殖信号非常重要。有趣的是，基于 RNAi 的黏着斑激酶沉默或使用小分子抑制剂（FAKi）的抑制导致靶向细胞侵袭的阻断，并通过失活多种信号通路诱导细胞凋亡，包括经典和替代 NF-κB 通路。此外，伊布替尼和 FAKi 的联合治疗具有高度协同作用，并且可以克服套细胞淋巴瘤的伊布替尼耐药性。这些数据表明，黏着斑激酶对于套细胞淋巴瘤中基质介导的存活和耐药性非常重要，为靶向治疗策略提供了依据。
