Rituximab and obinutuzumab differentially hijack the B cell receptor and NOTCH1 signaling pathways
Jennifer Edelmann,
Arran D. Dokal,
Emma Vilventhraraja,
Karlheinz Holzmann,
David Britton,
Tetyana Klymenko,
Hartmut Döhner,
Mark Cragg,
Andrejs Braun,
Pedro Cutillas,
John G. Gribben
Affiliations
Jennifer Edelmann
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Department of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany; Corresponding author
Arran D. Dokal
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UK
Emma Vilventhraraja
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Karlheinz Holzmann
Center for Clinical Research, Genomics Core Facility, Ulm University, Helmholtzstr. 8/1, 89081 Ulm, Germany
David Britton
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UK
Tetyana Klymenko
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Sheffield Hallam University, City Campus, Howard Street, Sheffield, S1 1WB, UK
Hartmut Döhner
Department of Internal Medicine III, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, Germany
Mark Cragg
Antibody and Vaccine Group, Centre for Cancer Immunology, University of Southampton Faculty of Medicine, Tremona Road, Southampton, SO16 6YD, UK
Andrejs Braun
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Pedro Cutillas
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK; Kinomica Limited, Biohub Alderley Park, Alderley Edge, Macclesfield, Cheshire, SK10 4TG, UK
John G. Gribben
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
Summary: The anti-CD20 monoclonal antibodies rituximab and obinutuzumab differ in their mechanisms of action, with obinutuzumab evoking greater direct B cell death. To characterize the signaling processes responsible for improved B cell killing by obinutuzumab, we undertook a phosphoproteomics approach and demonstrate that rituximab and obinutuzumab differentially activate pathways downstream of the B cell receptor. Although both antibodies induce strong ERK and MYC activation sufficient to promote cell-cycle arrest and B cell death, obinutuzumab exceeds rituximab in supporting apoptosis induction by means of aberrant SYK phosphorylation. In contrast, rituximab elicits stronger anti-apoptotic signals by activating AKT, by impairing pro-apoptotic BAD, and by releasing membrane-bound NOTCH1 to up-regulate pro-survival target genes. As a consequence, rituximab appears to reinforce BCL2-mediated apoptosis resistance. The unexpected complexity and differences by which rituximab and obinutuzumab interfere with signaling pathways essential for lymphoma pathogenesis and treatment provide important impetus to optimize and personalize the application of different anti-CD20 treatments.