Cerdulatinib Induces Bim Expression And Synergistic Cell Kill In Combination With Venetoclax In Follicular Lymphoma Cell Lines

Follicular lymphoma (FL) is the most frequently occurring indolent B-cell non-Hodgkin lymphoma. Treatment typically involves rituximab in combination with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), or CVP (cyclophosphamide, vincristine, and prednisone). Disease relapse is high, and current treatment options for these patients are limited. BTK inhibition has limited clinical activity in FL patients, and while the PI3Kδ inhibitor idelalisib was recently approved, tolerability has been an issue. Limited clinical activity was observed with the Bcl-2 inhibitor venetoclax, due to a compensatory upregulation of Mcl-1 by the tumor cell. Consequently, novel treatment strategies are required for patients with relapsed/refractory FL. Cerdulatinib is a dual SYK/JAK inhibitor that targets the BCR and cytokine signaling pathways. We previously demonstrated in chronic lymphocytic leukemia (CLL) cells that cerdulatinib inhibited signaling via the BCR and IL-4 signaling pathways and induced apoptosis in a dose- and time-dependent manner. However, the mechanism behind cerdulatinib-induced tumor killing has not previously been investigated. Herein we explore the function of cerdulatinib alone and in combination with venetoclax for the treatment of FL. To confirm cerdulatinib activity in FL derived cells lines WSU-FSCCL, DOHH2 and SU-DHL6, cells were incubated with cerdulatinib prior to BCR or cytokine receptor engagement. Cerdulatinib (0.1-1µM) significantly inhibited anti-Ig-induced pAKTS473, pERKThr202/Tyr204, pS6 ribosomal subunit Ser235/236 and cytokine-induced STAT signaling. The Bcl-2 protein was highly expressed in all cell lines consistent with a t(14:18) translocation, whereas basal Mcl-1 was expressed at lower levels. Bcl-2 levels remained unchanged following cerdulatinib treatment in all three cell lines. However, in contrast to CLL where cerdulatinib inhibited Mcl-1 expression, modulation of Mcl-1 protein expression by cerdulatinib in FL cell lines was subtle and inconsistent. Cerdulatinib alone induced 12%-44% cell death in all cell lines tested in a time dependent manner (24-72h) and this correlated with a robust increase in Bim expression at the RNA and protein level. We subsequently treated DOHH2, WSU-FSCCL and DHL6 cells with cerdulatinib in combination with 10-100nM venetoclax. Venetoclax synergized with cerdulatinib to induce significantly greater levels of apoptosis in all cell lines investigated compared to either agent alone and appeared to function by displacing Bim from Bcl-2. To demonstrate in vivo capability, we xenografted SU-DHL6 subcutaneously in nude mice. Cerdulatinib in combination with venetoclax led to greater antitumor activity when compared to vehicle or either drug alone. Together these data highlight a rationale for combining cerdulatinib with venetoclax for the treatment of FL. Citation Format: Andrew J. Steele, Greg Coffey, JiaJia Feng, Matthew D. Blunt, Francis DeGuzman, Deogracias Canivel, Jack Rose, Kenneth Der, Janet Leeds, Anjali Pandey, Pamela Conley. Cerdulatinib induces Bim expression and synergistic cell kill in combination with venetoclax in follicular lymphoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 305.