title: Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex.
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 ofde novoenhancer 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. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Jon S
authors.initials: JS
authors.lastname: Zawistowski
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Bevill
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goulet
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Stuhlmiller
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Beltran
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Olivares-Quintero
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Darshan
authors.initials: D
authors.lastname: Singh
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Noah
authors.initials: N
authors.lastname: Sciaky
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Parker
authors.affiliation: Department of Biostatistics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Naim U
authors.initials: NU
authors.lastname: Rashid
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: James S
authors.initials: JS
authors.lastname: Duncan
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Whittle
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Angus
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Sara Hanna
authors.initials: SH
authors.lastname: Velarde
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Golitz
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Xiaping
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Charlene
authors.initials: C
authors.lastname: Santos
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Department of Surgery, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Kristalyn
authors.initials: K
authors.lastname: Gallagher
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Graves
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.affiliation: Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Carey
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.|Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.affiliation: Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina. gary_johnson@med.unc.edu.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000070819:Discoidin Domain Receptor 1 / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D034622:RNA Interference; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D000970:Antineoplastic Agents; D001381:Azepines; D018797:Cell Cycle Proteins; D000070819:Discoidin Domain Receptor 1; D006576:Heterocyclic Compounds, 4 or More Rings; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D011728:Pyridones; D011744:Pyrimidinones; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A; C560077:trametinib; C482128:MAP2K2 protein, human; C092030:DDR1 protein, human; C482125:MAP2K1 protein, human