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 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. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 235.

• Authors: Jon S Zawistowski, Samantha M Bevill, Daniel R Goulet, Timothy J Stuhlmiller, Adriana S Beltran, Jose F Olivares-Quintero, Darshan Singh, Noah Sciaky, Joel S Parker, Naim U Rashid, Xin Chen, James S Duncan, Martin C Whittle, Steven P Angus, Sara Hanna Velarde, Brian T Golitz, Xiaping He, Charlene Santos, David B Darr, Kristalyn Gallagher, Lee M Graves, Charles M Perou, Lisa A Carey, H Shelton Earp, Gary L Johnson
• Journal: Cancer discovery (Cancer Discov) Vol. 7 Issue 3 Pg. 302-321 (03 2017) ISSN: 2159-8290 [Electronic] United States
• PMID: 28108460 (Publication Type: Clinical Trial, Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• (+)-JQ1 compound
• Antineoplastic Agents
• Azepines
• BRD4 protein, human
• Cell Cycle Proteins
• GSK1210151A
• Heterocyclic Compounds, 4 or More Rings
• Nuclear Proteins
• Pyridones
• Pyrimidinones
• Transcription Factors
• Triazoles
• trametinib
• MAP2K2 protein, human
• DDR1 protein, human
• Discoidin Domain Receptor 1
• Positive Transcriptional Elongation Factor B
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP2K1 protein, human

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Azepines (pharmacology, therapeutic use)
• Cell Cycle Proteins
• Cell Line, Tumor
• DNA Methylation
• Discoidin Domain Receptor 1 (genetics)
• Drug Resistance, Neoplasm
• Drug Synergism
• Enhancer Elements, Genetic
• Epigenesis, Genetic
• Female
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors)
• MAP Kinase Kinase 2 (antagonists & inhibitors)
• Mice, Inbred BALB C
• Mice, SCID
• Molecular Targeted Therapy
• Nuclear Proteins (antagonists & inhibitors)
• Positive Transcriptional Elongation Factor B (antagonists & inhibitors, genetics, metabolism)
• Pyridones (pharmacology, therapeutic use)
• Pyrimidinones (pharmacology, therapeutic use)
• RNA Interference
• Transcription Factors (antagonists & inhibitors)
• Triazoles (pharmacology, therapeutic use)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)
• Xenograft Model Antitumor Assays