Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment

// Ailin Guo 1,* , Pin Lu 1,* , Greg Coffey 2 , Pamela Conley 2 , Anjali Pandey 2 and Y. Lynn Wang 1 1 Department of Pathology, Lymphoma Translational Pathology, University of Chicago, Chicago, IL, USA 2 Portola Pharmaceuticals, Inc., South San Francisco, CA, USA * These authors have contributed equally to this study Correspondence to: Y. Lynn Wang, email: // Keywords : CLL, cerdulatinib, SYK, JAK-STAT, molecularly targeted therapy Received : December 21, 2016 Accepted : January 01, 2017 Published : January 10, 2017 Abstract Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Notably, cerdulatinib blocked proliferation of ibrutinib-resistant primary CLL cells and of BTK C481S -transfected/ibrutinib-resistant lymphoma cells. These anti-tumor effects are well correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.