Venetoclax resistance induced by activated T cells can be counteracted by sphingosine kinase inhibitors in chronic lymphocytic leukemia

SARAPURA MARTINEZ, VALERIA J.; BUONINCONTRO, BRENDA; CASSARINO, CHIARA; BERNATOWIEZ, JULIANA; COLADO, ANA; CORDINI, GREGORIO; CUSTIDIANO, MARIA DEL ROSARIO; MAHUAD, CAROLINA; PAVLOVSKY, MIGUEL A.; BEZARES, RAIMUNDO F.; FAVALE, NICOLÁS O.; VERMEULEN, MÓNICA; BORGE, MERCEDES; GIORDANO, MIRTA; GAMBERALE, ROMINA

Frontiers in Oncology

Frontiers media S.A.

Año: 2023 vol. 13

The treatment of chronic lymphocytic leukemia (CLL) patients with venetoclaxbasedregimens has demonstrated efficacy and a safety profile, but theemergence of resistant cells and disease progression is a current complication.Therapeutic target of sphingosine kinases (SPHK) 1 and 2 has opened newopportunities in the treatment combinations of cancer patients. We previouslyreported that the dual SPHK1/2 inhibitor, SKI-II enhanced the in vitro cell deathtriggered by fludarabine, bendamustine or ibrutinib and reduced the activationand proliferation of chronic lymphocytic leukemia (CLL) cells. Since wepreviously showed that autologous activated T cells from CLL patients favorthe activation of CLL cells and the generation of venetoclax resistance due to theupregulation of BCL-XL and MCL-1, we here aim to determine whether SPHKinhibitors affect this process. To this aim we employed the dual SPHK1/2 inhibitorSKI-II and opaganib, a SPHK2 inhibitor that is being studied in clinical trials. Wefound that SPHK inhibitors reduce the activation of CLL cells and the generationof venetoclax resistance induced by activated T cells mainly due to a reducedupregulation of BCL-XL. We also found that SPHK2 expression was enhanced inCLL cells by activated T cells of the same patient and the presence of venetoclax selects resistant cells with high levels of SPHK2. Of note, SPHK inhibitors wereable to re-sensitize already resistant CLL cells to a second venetoclax treatment.Our results highlight the therapeutic potential of SPHK inhibitors in combinationwith venetoclax as a promising treatment option for the patients.