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

Haematologica
Martina RudeliusAndreas Rosenwald

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...Continue Reading

Citations

May 9, 2018·Current Opinion in Hematology·Renée BeekmanElias Campo
Jul 22, 2019·Journal of Clinical Medicine·Antonio Giovanni SolimandoHermann Einsele
Apr 10, 2019·American Journal of Hematology·Preetesh Jain, Michael Wang
May 28, 2020·Journal of Clinical Medicine·Antonella ArgentieroNicola Silvestris
Feb 6, 2020·International Journal of Molecular Sciences·Anuvrat SircarNarendranath Epperla
Jul 16, 2020·Cancers·Antonio Giovanni SolimandoDomenico Ribatti
Oct 27, 2020·Canadian Journal of Gastroenterology & Hepatology·Antonella ArgentieroOronzo Brunetti
Mar 3, 2020·Translational Oncology·Tiziana AnneseDomenico Ribatti
Aug 31, 2020·Hematology/oncology Clinics of North America·Alba NavarroElías Campo
Aug 17, 2021·Frontiers in Cell and Developmental Biology·Shahrzad Jalali, Stephen M Ansell
Oct 29, 2021·Journal of Clinical and Experimental Hematopathology : JCEH·Kazuto TogitaniKensuke Kojima

❮ Previous
Next ❯

Methods Mentioned

BETA
immunoprecipitation
fluorescence microscopy

Software Mentioned

ZEISS
JEKO
MINO
MAVER
CalcuSyn

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Actin, Myosin & Cell Movement

Contractile forces generated by the actin-myosin cytoskeleton are critical for morphogenesis, but the cellular and molecular mechanisms of contraction have been elusive for many cell shape changes and movements. Here is the latest research on the roles of actin and myosin in cell movement.