Alisertib-Induced Polyploidy And Senescence In Dh/Dp-Dlbcl Is Abrogated By Synthetic Lethal Interactions With Ibrutinib And Rituximab

Diffuse Large B-cell Lymphoma (DLBCL) especially the double-hit (DH)/ double-protein (DP) DLBCL is an aggressive subtype of Non-Hodgkin Lymphoma (NHL). A majority of patients will fail frontline R-CHOP-like therapy and novel agents targeting MYC/BCL2 are needed. Aurora kinases are important regulators of mitosis, frequently over expressed and strongly associated with human cancers including DLBCL. Pre-clinical research and clinical studies have shown that aurora kinase inhibitors have a ~25-30% response rate in B- and T- NHL. Here, we show that alisertib-induced polyploidy and senescence are responsible for treatment failure and can be overcome by implementing a synthetic lethal approach by targeting Bruton's Tyrosine kinase (Btk) with ibrutinib and CD20 with rituximab.