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

被引：11

作者：

Elias, Esteban Enrique ^{[1
]}

Sarapura Martinez, Valeria Judith ^{[1
]}

Amondarain, Mikele ^{[1
]}

Colado, Ana ^{[1
]}

Cordini, Gregorio ^{[1
,2
]}

Bezares, Raimundo Fernando ^{[3
]}

Fernandez Grecco, Horacio ^{[4
]}

Custidiano, Maria del Rosario ^{[5
]}

Sanchez avalos, Julio Cesar ^{[5
]}

Garate, Gonzalo ^{[6
]}

Pavlovsky, Miguel A. ^{[7
]}

Borge, Mercedes ^{[1
,8
]}

Giordano, Mirta ^{[1
,8
]}

Gamberale, Romina ^{[1
,8
]}

机构：

[1] Acad Nacl Med ANM, CONICET, Inst Med Expt IMEX, Lab Inmunol Oncol, Pacheco de Melo 3081, RA-1425 Buenos Aires, DF, Argentina

[2] Univ Buenos Aires, Hosp Clin Jose de San Martin, Buenos Aires, DF, Argentina

[3] Hosp Gen Agudos Dr Teodoro Alvarez, Buenos Aires, DF, Argentina

[4] Sanatorio Municipal Dr Julio Mendez, Buenos Aires, DF, Argentina

[5] Inst Alexander Fleming, Buenos Aires, DF, Argentina

[6] Hosp Aleman, Buenos Aires, DF, Argentina

[7] CABA, FUNDALEU, Buenos Aires, DF, Argentina

[8] Univ Buenos Aires, Fac Med, Dept Microbiol Parasitol & Inmunol, RA-2155 Buenos Aires, DF, Argentina

来源：

CANCER IMMUNOLOGY IMMUNOTHERAPY | 2022年 / 71卷 / 04期

关键词：

CLL; Venetoclax resistance; Entospletinib-Idelalisib; Ibrutinib-Acalabrutinib; KINASE INHIBITORS; LEUKEMIA; RITUXIMAB; IBRUTINIB; BCL2;

D O I：

10.1007/s00262-021-03043-x

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (PI3K delta) 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.

引用

页码：979 / 987

页数：9

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