Abstract 1757: The novel BTK inhibitor CC-292 exerts in vitro and in vivo antitumor activity, interferes with adhesion, cell migration, and synergizes with lenalidomide in MCL models
Authors: Vidal-Crespo Anna , Rodríguez Vanina , Matas-Céspedes Alba , Campos Elías , López-Guillermo Armando , Roué Gael , Colomer Dolors , Pérez-Galán Patricia 
Published: May 2015

Background

B-cell receptor (BCR) signaling contributes to the pathogenesis of B cell malignancies and has emerged as a new target for therapy with special relevance for tumor cell-microenvironment crosstalk. Recently, blockade of the BCR-related kinase Btk (Bruton tyrosin kinase) with the first-in-class inhibitor Ibrutinib, has shown impressive clinical responses in Mantle cell lymphoma (MCL) and Chronic Lymphocytic Leukemia. However, resistances to treatment have already appeared, opening the door to new BTK inhibitors. In this study, we have evaluated the antitumor profile of a novel and highly selective BTK inhibitor CC-292(Celgene)in MCL.

Methods

Representative MCL lines (MINO, JEKO-1, REC-1, UPN1, Z138, HBL2, GRANTA, JVM-2) were used for in vitro and in vivo studies. The effects of CC-292 on lymphoma cell growth and apoptosis were analyzed by MTT and Annexin V/PI staining, respectively. BTK phosphorylation at Y223 residue was used as a read-out of BTK activity. Microenvironment-derived BTK activation was mimicked by IgM crosslinking or SDF1α/CXCL12 stimulation. Actin polymerization experiments were performed using Phalloidin-TRITC staining, and adhesion assays were done on EIA/RIA 96-well plates coated with Fibronectin or VCAM-1. In vivo activity was assessed in a subcutaneous mouse xenograft model, where daily oral dosing was started when tumors were palpable and extended for a total of 18 days.

Results

BTK activation (pBtkY(223)) was detected in all MCL cell lines analyzed. CC-292 (10-1000nM) exerted cytostatic effect in part of the cell lines, where REC-1, MINO, JVM2 and UPN1 were the most sensitive cell lines. No correlation between constitutive Btk activation and response to CC-292 was found. Noteworthy, CC-292 potently inhibited constitutive and IgM/CXCL12-induced Btk activation and interfered with tumor cell-microenvironment interactions, by blocking SDF1α/CXCL12-induced actin polymerization, as well as IgM-induced adhesion to VCAM and FN. In CC-292 sensitive cell lines, the combination with the immunomodulatory drug lenalidomide was synergistic and was accompanied with IRF4 decrease in MINO and REC cell lines. Finally, CC-292 (30mg/kg) showed antitumor activity in vivo in a sc mouse xenograft (UPN-1 cell line), reducing tumor outgrowth by 52%

Conclusions

In summary, these results warrant further investigation of CC-292 for MCL therapy, both alone and in combination with the immunomodulatory agent lenalidomide.

Citation Format: Anna Vidal-Crespo, Vanina Rodríguez, Alba Matas-Céspedes, Elías Campos, Armando López-Guillermo, Gael Roué, Dolors Colomer, Patricia Pérez-Galán. The novel BTK inhibitor CC-292 exerts in vitro and in vivo antitumor activity, interferes with adhesion, cell migration, and synergizes with lenalidomide in MCL models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1757. doi:10.1158/1538-7445.AM2014-1757