LAUSR

A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter's Syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex-vivo and in vivo efficacy of the dual PI3K-d/g inhibitor Duvelisib (Duv) and the Bcl-2 inhibitor Venetoclax (Ven) using four different RS-patient-derived xenograft (PDX) models. Ex-vivo exposure of RS cells to Duv, Ven or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. While RS1316, IP867/17 and RS9737 cells express PI3K-d, PI3K-g and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-g and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof-of-concept of the efficacy of dual targeting of PI3K-d/g and Bcl-2 in RS, opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are underway (NCT03892044).