Abstract LB-239: An rnai sensitization screen identifies compensatory IKKα activation during IKKβ inhibition

Introduction: We previously described a subtype of diffuse large B-cell lymphoma (DLBCL) termed activated B-cell-like (ABC) DLBCL that depends on NF-κB activity for survival, and showed that a specific small molecule inhibitor of the upstream kinase IKKβ is selectively toxic to this subgroup of lymphoma. Methods: To identify proteins or pathways whose inhibition may synergize with the toxicity of IKKβ inhibition in ABC DLBCL, we performed an “RNAi sensitization” screen with an RNA interference library, directed against 500 protein kinases, in the presence of the specific IKKβ inhibitor in an ABC DLBCL cell line. Results: Short hairpin RNA (shRNAs) targeting IKKα, a component of the IKK complex, enhanced killing by the IKKβ inhibitor in ABC DLBCL cell lines but not other lymphoma cell lines. Gene expression profiling and NF-κB-specific reporter assays showed that IKKα shRNA affects the classical NF-κB pathway, further inhibiting the phosphorylation of IκBα only in the presence of the specific IKKβ inhibitor. Further studies in physiologic models of lymphocyte stimulation showed that compensatory IKKα activity occurs in other settings. Conclusions: These results demonstrate that loss-of-function screens in the presence of a defined inhibitor can identify therapeutic targets in cancers, providing a rationale for combination therapies targeting multiple pathways critical to an individual cancer.