Abstract 4944: Combined treatment of BTK and PI3K inhibitors synergistically disrupts BCR-signaling, overcomes microenviroment-mediated survival and drug resistance in mantle cell lymphoma.
Authors: Tao Jiangchuan , Lwin Tint , Zhao Xiaohong , Shah Bijal , Zhang Ling , Moscinski Lynn , Dalton William , Sotomayor Eduardo M. , Tao Jianguo 
Published: August 2014

Mantle cell lymphoma (MCL) is recognized as an aggressive lymphoma characterized by overexpression of cyclin D1 as a result of t (11:14) translocation. It carries poor prognosis due to the emergence of drug resistance and currently no effective cure is available for this disease. Dynamic interactions between the lymphoma cell and its microenvironment play a critical role in lymphoma development and response to therapy. Recently, inhibitors of BCR signaling have become an area of substantial clinical interest. B-cell receptor (BCR) provides essential growth and survival signals to lymphomas. We therefore studied the role of BCR signal pathways in stroma mediated survival and drug resistance of mental cell lymphoma.

We demonstrate that all mantle cell lymphoma cell lines and primary MCL cells express key BCR downstream signaling molecules, BTK (Bruton's tyrosine kinase), AKT and ERK, in activated (phosphorylated) form. Phosphorylation statutes of pBTK, pAKT and pERK are further up regulated upon adhesion to lymph node stroma cells. Cell adhesion between lymphoma cells and tumor stroma cells is essential for tumor cell survival and drug resistance. Inhibition of BTK by PCI 32765 or PI3Kδ by CAL101 abolishes intrinsic as well as stroma induced activation of BTK, AKT, ERK. It also significantly disrupts tumor - stromal cell adhesion and induces cell apoptosis. Moreover, combined treatment of PCI 32765 and CAL101 synergetically inhibit BCR signaling and induce cell apoptosis in absence and presence of HK stroma cells.

CXCR4 has been reported to play a critical role in lymphoma cell homing, migration, and adhesion. We evaluated CXCR4 expression upon MCL adhesion to stroma cells. We demonstrate that the CXCR4 level was significantly increased in Jeko-1 and HBL2 cell lines and primary MCL cells when co-cultured with HK stroma cells. The stroma cells-induced CXCR4 increase was significantly abolished by BCR signaling inhibitors, PCI 32765 and Cal101.

We further explored the effect of those inhibitors on cyclin D1. We show that cyclin D1 is constitutively expressed in MCL cell lines and primary MCL cells and that its expression was further increased when co-cultured with HK stoma cells. Both PCI 32765 and Cal101 decreased intrinsic cyclin D1 expression in the absence and presence of HK cells. Furthermore, combined treatment of PCI 32765 and Cal101 more strikingly attenuated cyclin D1 expression than either agent alone.

Collectively, Our study demonstrates (1) the constitutive expression and biological function of BCR signaling in MCL, (2) the essential role of BCR signaling in microenvironment (stroma cell) mediated MCL survival, adhesion and drug resistance, and (3) the therapeutic potential of using novel BCR inhibitors, PCI 32765 and Cal101, in single or combine for MCL therapy.

Citation Format: Jiangchuan Tao, Tint Lwin, Xiaohong Zhao, Bijal Shah, Ling Zhang, Lynn Moscinski, William Dalton, Eduardo M. Sotomayor, Jianguo Tao. Combined treatment of BTK and PI3K inhibitors synergistically disrupts BCR-signaling, overcomes microenviroment-mediated survival and drug resistance in mantle cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4944. doi:10.1158/1538-7445.AM2013-4944