Venetoclax As a Single Agent and in Combination with PI3K-mTOR1/2 Kinase Inhibitors Against Ibrutinib Sensitive and Resistant Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma and prognosis remains poor in MCL patients due to minimal residual disease (MRD), subsequent emergence of drug resistance and lymphoma progression. Ibrutinib is a bruton's tyrosine kinase (BTK) inhibitor that has high response rates in patients with MCL, however, over 30% of MCL patients showed partial or complete lack of response to ibrutinib and experienced disease progression within 12 months of treatment. Alarmingly, once patients relapse after ibrutinib treatment, the 1-year survival rate is only 22%. Our study demonstrated that the major hallmarks of ibrutinib resistant (IR) MCL are increased mitochondrial apoptosis priming, increased BCL-2 dependence, and sustained PI3K-AKT-mTOR pathway activation accompanied by enhanced stromal cell interaction. Sustained BCL-2 and PI3K-AKT-mTOR pathways cooperatively dictate interaction (adhesion) between MCL and stroma, promote MCL IR and proliferation. Disruption of both pathways establishes a novel 'triple-hit' or 'multi-hit' strategy: targeting the pathway (BCL-2) related to survival, targeting the pathway (PI3K-mTOR) related to cell proliferation, culminating in disruption of the lymphoma-stroma adhesion/interaction to sensitize and enhance cytotoxicity. BEZ235 and AZD8055 synergized with ABT-199 to suppress MCL viability and attenuated clonogenic growth in both ibrutinib sensitive and resistant MCL lines and primary cells. Moreover, we observed that compensatory upregulation of MCL1 following ABT-199 exposure could be abrogated by BEZ235 and AZD8055 - both in ibrutinib sensitive and IR cells. The combination of BEZ235 and AZD8055 with ABT-199 triggered a more dramatic reduction of MCL-1 protein expression, accompanied by an increase in apoptotic PARP cleavage, both in IR MCL cell lines and primary MCL. Together, these data suggest a novel strategy to overcome the dismal prognosis associated with IR.