Q: Why is this topic important to explore?
A: The CD20 protein found on the surface of mature B cells is involved in the regulation of B cell differentiation and is a well-established target for anti-CD20 therapy in the treatment of B cell malignancies. Drug resistance to these antibodies, including rituximab and obinutuzumab, remains an ongoing challenge in the treatment of non-Hodgkin lymphoma. Many patients will become resistant to these commonly used antibodies. However, the mechanisms responsible for this resistance are unclear. It was our aim to define the immuno-biological landscape associated with this resistance.
Q: Tell us about the work and what you and your colleagues found.
A: We conducted detailed systems biology analyses and immune functional studies in rituximab-resistant and obinutuzumab-resistant cell lines in non-Hodgkin lymphoma models. We found that cells were associated with downregulation of immune signaling pathways, cytokine hyposecretion, and upregulation of B cell receptor signaling. Biological changes indicated that loss of CD20 was associated with decreased calcium signaling, which was accompanied by depolarized membrane and persistent activation of BTK signaling pathway as possible mechanisms for anti-CD20 resistance. Furthermore, concomitant use of BTK inhibitor and hyperpolarizing agents resulted in restoration of calcium signaling and markedly increased cell death in CD20 resistant cells in both in vitro and in in vivo tumor xenograft models.
Q: Why are these results significant?
A: These data delineate that reduced calcium signaling is an important pathway in anti-CD20 resistance and is responsible for depolarization of cell membranes by altering the electrical activity and “turning on” BTK dependent survival pathways. In addition, these mechanisms may serve as a highly novel target for the treatment of CD20 resistant non-Hodgkin lymphomas.
Aside from Evens, other authors on the work are Ravi Dashnamoorthy, PhD, Rutgers Cancer Institute; Saheli Sarkar, PhD, Northeastern University, Boston, MA; Afshin Beheshti, PhD, Wyle Labs, NASA Ames Research Center, Mountain View, CA; Maisarah Mokhtar, BS, Rutgers Cancer Institute; Tali Konry, PhD, Northeastern University, Boston, MA; and Michael Levin, PhD, Tufts University, Medford, MA. Author disclosures and other details can be found here: (https://ash.confex.com/ash/2019/webprogram/Paper126539.html).
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