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Zawistowski JS , Bevill SM , Goulet DR , Stuhlmiller TJ , Beltran AS , Olivares-Quintero JF , Singh D , Sciaky N , Parker JS , Rashid NU , Chen X , Duncan JS , Whittle MC , Angus SP , Velarde SH , Golitz BT , He X , Santos C , Darr DB , Gallagher K , Graves LM , Perou CM , Carey LA , Earp HS , Johnson GL
Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex
Cancer Discov. 2017 Mar;7(3) :302-321
PMID: 28108460    PMCID: PMC5340640   
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Abstract
Targeting the dysregulated BRAF-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRAF and MEK, resistance develops often involving nongenomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in patients with triple-negative breast cancer (TNBC) induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTK) comparing tumor samples before and after one week of treatment. In preclinical models, MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation, and p300 that drives transcriptional adaptation. Inhibition of the P-TEFb-associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts, and syngeneic mouse TNBC models. Pharmacologic targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance.Significance: Widespread transcriptional adaptation to pharmacologic MEK inhibition was observed in TNBC patient tumors. In preclinical models, MEK inhibition induces dramatic genome-wide modulation of chromatin, in the form of de novo enhancer formation and enhancer remodeling. Pharmacologic targeting of P-TEFb complex members at enhancers is an effective strategy to durably inhibit such adaptation. Cancer Discov; 7(3); 302-21. (c)2017 AACR.This article is highlighted in the In This Issue feature, p. 235.
Notes
2159-8290 Zawistowski, Jon S Bevill, Samantha M Goulet, Daniel R Stuhlmiller, Timothy J Beltran, Adriana S Olivares-Quintero, Jose F Singh, Darshan Sciaky, Noah Parker, Joel S Rashid, Naim U Chen, Xin Duncan, James S Whittle, Martin C Angus, Steven P Velarde, Sara Hanna Golitz, Brian T He, Xiaping Santos, Charlene Darr, David B Gallagher, Kristalyn Graves, Lee M Perou, Charles M Carey, Lisa A Earp, H Shelton Johnson, Gary L F31 GM116534/GM/NIGMS NIH HHS/United States P50 CA058223/CA/NCI NIH HHS/United States R01 GM101141/GM/NIGMS NIH HHS/United States Journal Article United States Cancer Discov. 2017 Mar;7(3):302-321. doi: 10.1158/2159-8290.CD-16-0653. Epub 2017 Jan 20.