title: Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.
abstract: Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+B-cell malignancies.
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: B
authors.initials: B
authors.lastname: Cui
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Wu
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: M Y
authors.initials: MY
authors.lastname: Choi
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Widhopf Ii
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis; D049109:Cell Proliferation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D000071818:Wnt-5a Protein / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C107953:RAC1 protein, human; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C551803:ibrutinib; C078716:ROR1 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D020830:rac1 GTP-Binding Protein; D000225:Adenine