DGKα inhibition enhances the antitumor effect of chiauranib on transformed follicular lymphoma.

Abstract

Transformed follicular lymphoma (t-FL) is a heterogeneous, aggressive B-cell malignancy with unfavorable clinical outcomes, while there is no standard and effective treatment available for t-FL. In this study, we investigated the preclinical anti-lymphoma efficacies and potential mechanism of action for a novel therapeutic strategy, combining the DGKα inhibitor ritanserin with chiauranib, a new orally bioavailable multi-target kinase inhibitor, in t-FL models. This combination therapy exhibited synergistic cytotoxicity against t-FL cells and primary B lymphoma cells, evidenced by cooperatively inducing loss of cell viability and promoting cell apoptosis. Moreover, the combination of ritanserin with chiauranib resulted in significant suppression of tumor burden in xenograft models. The synergistic lethality of ritanserin and chiauranib in t-FL was associated with the synergistic effect of these two medications on the inhibition of their respective targets. Of importance, the combined treatment was dual blockade of PI3K/AKT/mTOR and RAF/MEK/ERK pathways as well as vertical targeting of DGKα. Besides, downregulating the levels of c-Myc, BCL-xL and MCL-1 also contributed to the synergistic effects of the combined regimen on t-FL. Taken together, these findings suggest that the synergy between the DGKα inhibitor ritanserin and multi-targeted inhibitor chiauranib might represent a promising option for the treatment of t-FL.