BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models

Drug-tolerant “persister” tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones...

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Published in:	Cancer cell 2019-05, Vol.35 (5), p.752-766.e9
Main Authors:	Zhao, Xiaohong, Ren, Yuan, Lawlor, Matthew, Shah, Bijal D., Park, Paul M.C., Lwin, Tint, Wang, Xuefeng, Liu, Kenian, Wang, Michelle, Gao, Jing, Li, Tao, Xu, Mousheng, Silva, Ariosto S., Lee, Kaplan, Zhang, Tinghu, Koomen, John M., Jiang, Huijuan, Sudalagunta, Praneeth R., Meads, Mark B., Cheng, Fengdong, Bi, Chengfeng, Fu, Kai, Fan, Huitao, Dalton, William S., Moscinski, Lynn C., Shain, Kenneth H., Sotomayor, Eduardo M., Wang, Gang Greg, Gray, Nathanael S., Cleveland, John L., Qi, Jun, Tao, Jianguo
Format:	Article
Language:	eng
Subjects:	ABT-199 BCL2 CDK7 double-hit lymphoma drug persister drug resistance mantle cell lymphoma super-enhancer remodeling THZ1 transcriptome reprogramming
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Summary:	Drug-tolerant “persister” tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas. [Display omitted] •Unified genetic and non-mutational mechanisms drive ABT-199 resistance in lymphoma•Rare lymphoma cells having BCL2 amplicon loss are selected during ABT-199 treatment•CDK7-dependent transcriptional reprogramming contributes to ABT-199 resistance•CDK7 inhibition prevents and overcomes ABT-199 resistance in B cell lymphoma models Zhao et al. show that resistance to the BCL-2 inhibitor ABT-199 is conferred by super enhancer reprogramming and loss of BCL2 amplicons in models of mantle cell lymphoma and double hit lymphoma. Combining ABT-199 with the CDK7 inhibitor THZ1 prevents or reverses BCL-2 inhibitor resistance.
ISSN:	1535-6108 1878-3686