The Bruton tyrosine kinase inhibitor, ibrutinib, has shown high response rates in mantle cell lymphoma (MCL); however, many ibrutinib-treated MCL patients relapse with resistance and fulminant progression. Recently, we modelled acquired ibrutinib resistance (IR) by generating ibrutinib resistant MCL cell lines (Zhao, et al 2017). Using chemical proteomics and cell-based drug screen assay for drug sensitivity and response, we determined the key kinase signalling associated with IR development and revealed that adaptive kinome reprogramming contributes to increased proliferation and IR. Among the global kinase changes, sustained PI3K-AKT-MTOR pathway activation was shown to be a central hub for kinome signalling and a major determinant for cell survival, proliferation and interaction of MCL cells with tumour microenvironment (TME) stromal cells in IR MCL (Shain and Tao 2014). These results warranted the design of mechanism-driven PI3K-MTOR inhibitionbased combination therapies against MCL.

The BCL2 family proteins mediate an intrinsic, mitochondrial apoptosis pathway. BCL2, BCL-xL (also termed BCL2L1), and MCL1 are antiapoptotic BCL2 family proteins (Davids and Letai 2012). These proteins suppress apoptosis by sequestering the BH3-only protein BIM (BCL2L11), which activates mitochondrial outer membrane permeabilization by the