Cirmtuzumab inhibits ibrutinib-resistant, Wnt5a-induced Rac1 activation and proliferation in mantle cell lymphoma

// Jian Yu 1, * , Yun Chen 1, * , Liguang Chen 1, * , Ling Zhang 1 , Laura Z. Rassenti 1 , George F. Widhopf II 1 and Thomas J. Kipps 1 1 Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA * These authors contributed equally to this work Correspondence to: Thomas J. Kipps, email: tkipps@ucsd.edu Keywords: cirmtuzumab; ibrutinib; Wnt5a; ROR1; MCL Received: December 07, 2017      Accepted: March 21, 2018      Published: May 15, 2018 ABSTRACT Cirmtuzumab may enhance the therapeutic activity of ibrutinib by inhibiting ROR1-dependent signaling pathway in patients with chronic lymphocytic leukemia (CLL). Mantle cell lymphoma (MCL) is B-cell malignancy that also expresses ROR1. In this study, we found that the plasma of patients with MCL had high levels of Wnt5a, a ROR1 ligand, that were comparable to those found in patients with CLL; in contrast Wnt5a was virtually undetectable in the plasma of age-matched healthy adults. We also found that Wnt5a induced Rac1 activation in the primary MCL cells. Cirmtuzumab, but not ibrutinib, could inhibit the capacity of Wnt5a to induce primary MCL cells to activate Rac1. Addition of exogenous Wnt5a in vitro significantly enhanced the numbers of MCL cell divisions and the proportion of dividing MCL cells entering S/G2 in MCL cells over time in the presence of CD154 and IL-4/10. Treatment of the MCL cells with cirmtuzumab, but not ibrutinib, blocked Wnt5a-enhanced proliferation of MCL cells. This study indicates that cirmtuzumab and ibrutinib may have complementary activity in the treatment of patients with MCL.