Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment

Abstract

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.

Mantle cell lymphoma: 2019 update on the diagnosis, pathogenesis, prognostication, and management

“…This feature in MCL provides activation signals to MCL cells and is involved in drug resistance. Targeting various components of BCR signaling and interactions with stromal cells has a great potential to overcome treatment resistance and eradicate dormant residual cells in MCL . Additional studies on the cytokine‐chemokine milieu and its interaction with MCL cells and stromal cells are needed to fully understand the MCL tissue microenvironment.…”

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

“…4 Despite these encouraging results, responses to ibrutinib treatment are variable/incomplete and show drug-resistance and population/genetic alterations stemming from unknown causes. 11,12 BCR signaling, initiated by self-antigen reactivity of BCR or by mutation in MYD88, activates both NF-κB in the ABC-DLBCL survival pathway and the phosphatidylinositol-3-kinase (PI3K) signaling pathway. 7,13,14 The class-I subPI3K family includes the alpha-, beta-, gamma-, and delta isoforms, which are often constitutively activated in cancer.…”

Bone metastasis as primary presentation of pancreatic ductal adenocarcinoma: A case report and literature review

“…[17][18][19][20] Thus, several approaches have been envisioned in order to molecularly overcome this malignant phenotype, in order to target both the cancer cells and the tumoral milieu. [21][22][23] Variable incidence of bone metastases from PDAC reported in literature (from 5% to 20%) should be conditioned by either the possible overlapping between symptoms related to the primary tumor and bone localization or the longer survival obtained in the last few years due the availability of new and more active chemotherapy regimens in both adjuvant and advanced settings. 6,[24][25][26][27] The predominance of osteolytic or osteoblastic bone metastasis is controversial in these patients.…”