Targeting WEE1 in diffuse large B-cell lymphoma: mediator in DNA damage and apoptosis

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of non-Hodgkin lymphoma. The current treatment for the disease currently cures only 60% of the patients, which means new therapies are needed to improve patient survival. In this project, we performed a large gene expression analysis in 1800 DLBCL patient samples to find new targets to improve the current treatment. Here we found high expression of the WEE1 protein, which is involved in cell cycle regulation and repair of DNA damage. Inhibition of the WEE1 protein in DLBCL cell lines induced disruption of the normal cell cycle and high levels of DNA damage, eventually causing cell death. In addition, WEE1 inhibition showed to enhance the currently used therapies for the treatment of DLBCL, which include rituximab (anti-CD20), radiation, CHOP (first line chemotherapy) and cytarabine (second line chemotherapy). Based on these findings, we also investigated the effect of WEE1 inhibition in combination with so-called “anti-apoptotic inhibitors”, which prevent cells from protecting themselves against cell death. These inhibitors are currently being tested in clinical trials for different types of non-Hodgkin lymphoma and leukemia’s, including DLBCL . We found that WEE1 inhibition worked very well together with the anti-apoptotic inhibitors, and that combination therapy significantly enhanced cell death in DLBCL. In total, our results demonstrate that inhibition of WEE1 is very successful in DLBCL, and would likely improve the current treatment available for DLBCL.