| Literature DB >> 31085176 |
Xiaohong Zhao1, Yuan Ren1, Matthew Lawlor2, Bijal D Shah3, Paul M C Park2, Tint Lwin1, Xuefeng Wang4, Kenian Liu5, Michelle Wang1, Jing Gao1, Tao Li6, Mousheng Xu2, Ariosto S Silva7, Kaplan Lee8, Tinghu Zhang2, John M Koomen9, Huijuan Jiang10, Praneeth R Sudalagunta7, Mark B Meads1, Fengdong Cheng11, Chengfeng Bi12, Kai Fu12, Huitao Fan13, William S Dalton3, Lynn C Moscinski5, Kenneth H Shain3, Eduardo M Sotomayor11, Gang Greg Wang13, Nathanael S Gray14, John L Cleveland15, Jun Qi16, Jianguo Tao17.
Abstract
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.Entities:
Keywords: ABT-199; BCL2; CDK7; THZ1; double-hit lymphoma; drug persister; drug resistance; mantle cell lymphoma; super-enhancer remodeling; transcriptome reprogramming
Year: 2019 PMID： 31085176 PMCID： PMC6945775 DOI： 10.1016/j.ccell.2019.04.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743