Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex

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 & 5 others Lee M. Graves, Charles M. Perou, Lisa A. Carey, H. Shelton Earp, Gary L. Johnson

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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.

LanguageEnglish (US)
Pages302-321
Number of pages20
JournalCancer Discovery
Volume7
Issue number3
DOIs
StatePublished - Mar 1 2017

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Positive Transcriptional Elongation Factor B
Mitogen-Activated Protein Kinase Kinases
Triple Negative Breast Neoplasms
Receptor Protein-Tyrosine Kinases
Neoplasms
p300-CBP Transcription Factors
Up-Regulation
Genome
MAP Kinase Signaling System
Acetylation
Heterografts
Epigenomics
Chromatin
Clinical Trials
Growth
trametinib

ASJC Scopus subject areas

  • Oncology

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Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. / 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.; Shelton Earp, H.; Johnson, Gary L.

In: Cancer Discovery, Vol. 7, No. 3, 01.03.2017, p. 302-321.

Research output: Contribution to journalArticle

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, Shelton Earp, H & Johnson, GL 2017, 'Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex' Cancer Discovery, vol. 7, no. 3, pp. 302-321. DOI: 10.1158/2159-8290.CD-16-0653
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. ; Shelton Earp, H. ; Johnson, Gary L./ Enhancer remodeling during adaptive bypass to MEK inhibition is attenuated by pharmacologic targeting of the P-TEFb complex. In: Cancer Discovery. 2017 ; Vol. 7, No. 3. pp. 302-321
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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.",
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AU - Stuhlmiller,Timothy J.

AU - Beltran,Adriana S.

AU - Olivares-Quintero,Jose F.

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AU - Sciaky,Noah

AU - Parker,Joel S.

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AU - Duncan,James S.

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AU - Angus,Steven P.

AU - Velarde,Sara Hanna

AU - Golitz,Brian T.

AU - He,Xiaping

AU - Santos,Charlene

AU - Darr,David B.

AU - Gallagher,Kristalyn

AU - Graves,Lee M.

AU - Perou,Charles M.

AU - Carey,Lisa A.

AU - Shelton Earp,H.

AU - Johnson,Gary L.

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