BCL-XL inhibition by BH3-mimetic drugs induces apoptosis in models of Epstein-Barr virus-associated T/NK-cell lymphoma.
Blood Adv
; 4(19): 4775-4787, 2020 10 13.
Article
in En
| MEDLINE
| ID: mdl-33017468
ABSTRACT
Epstein-Barr virus (EBV)-associated T- and natural killer (NK)-cell malignancies, such as extranodal NK-/T-cell lymphoma (ENKTL), exhibit high chemoresistance and, accordingly, such patients have a poor prognosis. The rare nature of such cancers and nonmalignant T/NK lymphoproliferative disorders, such as chronic active EBV (CAEBV), has limited our understanding of the pathogenesis of these diseases. Here, we characterize a panel of ENKTL- and CAEBV-derived cell lines that had been established from human tumors to be used as preclinical models of these diseases. These cell lines were interleukin-2 dependent and found to carry EBV in a latency II gene-expression pattern. All cell lines demonstrated resistance to cell death induction by DNA damage-inducing agents, the current standard of care for patients with these malignancies. This resistance was not correlated with the function of the multidrug efflux pump, P-glycoprotein. However, apoptotic cell death could be consistently induced following treatment with A-1331852, a BH3-mimetic drug that specifically inhibits the prosurvival protein BCL-XL. A-1331852-induced apoptosis was most efficacious when prosurvival MCL-1 was additionally targeted, either by BH3-mimetics or genetic deletion. Xenograft models established from the ENKTL cell line SNK6 provided evidence that A-1331852 treatment could be therapeutically beneficial in vivo. The data here suggest that therapeutic targeting of BCL-XL would be effective for patients with EBV-driven T/NK proliferative diseases, however, MCL-1 could be a potential resistance factor.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pharmaceutical Preparations
/
Epstein-Barr Virus Infections
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Blood Adv
Year:
2020
Type:
Article
Affiliation country:
Australia