Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype

SARAPURA MARTINEZ, VALERIA JUDITH; CORDINI, GREGORIO; CUSTIDIANO, MARIA DEL ROSARIO; PAVLOVSKY, MIGUEL A.; GAMBERALE, ROMINA; AMONDARAIN, MIKELE; BEZARES, RAIMUNDO FERNANDO; SÁNCHEZ ÁVALOS, JULIO CÉSAR; BORGE, MERCEDES; ELIAS, ESTEBAN ENRIQUE; COLADO, ANA; FERNANDEZ GRECCO, HORACIO; GARATE, GONZALO; GIORDANO, MIRTA

CANCER IMMUNOLOGY IMMUNOTHERAPY

SPRINGER

Año: 2021 vol. 71 p. 979 - 987

0340-7004

Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.