当前位置： SCI文献检索 > Cancer Discovery期刊下所有文献 > Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex.

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.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

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,Gr

doi

10.1158/2159-8290.CD-16-0653

subject

Has Abstract

pub_date

2017-03-01 00:00:00

pages

302-321

issue

3

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-16-0653

journal_volume

7

pub_type

临床试验,杂志文章

相关文献

Cancer Discovery文献大全
  • The OPCML tumor suppressor functions as a cell surface repressor-adaptor, negatively regulating receptor tyrosine kinases in epithelial ovarian cancer.

    abstract：UNLABELLED:Epithelial ovarian cancer is the leading cause of death from gynecologic malignancy, and its molecular basis is poorly understood. We previously demonstrated that opioid binding protein cell adhesion molecule (OPCML) was frequently epigenetically inactivated in epithelial ovarian cancers, with tumor suppress...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-11-0256

    authors： McKie AB,Vaughan S,Zanini E,Okon IS,Louis L,de Sousa C,Greene MI,Wang Q,Agarwal R,Shaposhnikov D,Wong JL,Gungor H,Janczar S,El-Bahrawy M,Lam EW,Chayen NE,Gabra H

    更新日期：2012-02-01 00:00:00

  • A critical role for fas-mediated off-target tumor killing in T cell immunotherapy.

    abstract：:T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-20-0756

    authors： Upadhyay R,Boiarsky JA,Pantsulaia G,Svensson-Arvelund J,Lin MJ,Wroblewska A,Bhalla S,Scholler N,Bot A,Rossi JM,Sadek N,Parekh S,Laganà A,Baccarini A,Merad M,Brown BD,Brody JD

    更新日期：2020-12-17 00:00:00

  • Serine biosynthesis is a metabolic vulnerability in FLT3-ITD-driven acute myeloid leukaemia.

    abstract：:Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITD) occurs in 30% of poor prognosis acute myeloid leukaemias (AMLs). Limited clinical efficacy of FLT3 inhibitors highlights the need for alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-dri...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-20-0738

    authors： Bjelosevic S,Gruber E,Newbold A,Shembrey C,Devlin JR,Hogg SJ,Kats L,Todorovski I,Fan Z,Abrehart TC,Pomilio G,Wei A,Gregory GP,Vervoort SJ,Brown KK,Johnstone RW

    更新日期：2021-01-12 00:00:00

  • Durable Responses with Brentuximab Vedotin in cHL.

    abstract：:According to survival results from a phase II trial of brentuximab vedotin, 34 patients with relapsed or refractory classic Hodgkin lymphoma had a complete response with this CD30-targeting antibody-drug conjugate; 13 remain in remission 5 years later. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-NB2016-100

    authors：

    更新日期：2016-09-01 00:00:00

  • CD10+GPR77+ Cancer-Associated Fibroblasts Promote Chemoresistance.

    abstract：:CD10 and GPR77 define a cancer-associated fibroblast (CAF) subset that sustains cancer stemness. ...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-RW2018-019

    authors：

    更新日期：2018-03-01 00:00:00

  • Antibody-Drug Conjugate Kills Neuroblastoma Cells.

    abstract：:Researchers have developed an antibody-drug conjugate with the potential to treat neuroblastoma. The agent targets ALK, which is found on neuroblastoma cells but not healthy cells, delivering a drug that causes DNA cross-links. Researchers have found that the antibody-drug conjugate kills ALK-expressing cells in vitro...

    journal_title：Cancer discovery

    pub_type： 评论,新闻

    doi：10.1158/2159-8290.CD-NB2019-052

    authors：

    更新日期：2019-06-01 00:00:00

  • Enzalutamide Bests Older NSAAs in mHSPC.

    abstract：:According to results from ENZAMET, a global phase III trial, adding enzalutamide to standard treatment for men with metastatic hormone-sensitive prostate cancer is superior in prolonging survival compared with older nonsteroidal antiandrogen drugs. ...

    journal_title：Cancer discovery

    pub_type： 评论,新闻

    doi：10.1158/2159-8290.CD-NB2019-066

    authors：

    更新日期：2019-08-01 00:00:00

  • Novel Mitochondrial Mechanisms of Cytarabine Resistance in Primary AML Cells.

    abstract：: Farge and colleagues describe a novel in vivo approach to identify and study primary acute myeloid leukemia (AML) cells that persist in the marrow after chemotherapy. They discovered that AML cells that persist in the mouse marrow after treatment with cytarabine have increased oxidative phosphorylation and that i...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-17-0476

    authors： Schimmer AD

    更新日期：2017-07-01 00:00:00

  • Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma.

    abstract：:MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arisin...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-19-0620

    authors： Muthalagu N,Monteverde T,Raffo-Iraolagoitia X,Wiesheu R,Whyte D,Hedley A,Laing S,Kruspig B,Upstill-Goddard R,Shaw R,Neidler S,Rink C,Karim SA,Gyuraszova K,Nixon C,Clark W,Biankin AV,Carlin LM,Coffelt SB,Sansom OJ,

    更新日期：2020-06-01 00:00:00

  • Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance.

    abstract：UNLABELLED:Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-11-0124

    authors： Tanaka K,Babic I,Nathanson D,Akhavan D,Guo D,Gini B,Dang J,Zhu S,Yang H,De Jesus J,Amzajerdi AN,Zhang Y,Dibble CC,Dan H,Rinkenbaugh A,Yong WH,Vinters HV,Gera JF,Cavenee WK,Cloughesy TF,Manning BD,Baldwin AS,Mi

    更新日期：2011-11-01 00:00:00

  • Gilead Buying Kite for $11.9 Billion.

    abstract：:Gilead Sciences will buy Kite Pharma-and its autologous CAR T-cell technology-for $11.9 billion. The acquisition will help Gilead build its oncology portfolio and boost its revenues. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-NB2017-123

    authors：

    更新日期：2017-10-01 00:00:00

  • ADC Could Benefit Some with Breast Cancer.

    abstract：:Results from a phase I/II trial suggest that an antibody-drug conjugate, sacituzumab govitecan, is active against refractory, metastatic triple-negative breast cancer. A phase III trial is under way to compare its safety and efficacy with that of standard chemotherapy. ...

    journal_title：Cancer discovery

    pub_type： 评论,新闻

    doi：10.1158/2159-8290.CD-NB2019-034

    authors：

    更新日期：2019-05-01 00:00:00

  • Stabilization of a closed kinase conformation induces RAF dimerization.

    abstract：:BRAF inhibitors stabilize a closed, rigid RAF kinase conformation that facilitates dimerization. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-RW2013-114

    authors：

    更新日期：2013-07-01 00:00:00

  • Entinostat plus exemestane has activity in ER+ advanced breast cancer.

    abstract：:Adding entinostat to exemestane improves survival in women with ER(+) advanced breast cancer. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-RW2013-101

    authors：

    更新日期：2013-07-01 00:00:00

  • ARID1A Deficiency Impairs the DNA Damage Checkpoint and Sensitizes Cells to PARP Inhibitors.

    abstract：UNLABELLED:ARID1A, SWI/SNF chromatin remodeling complex subunit, is a recently identified tumor suppressor that is mutated in a broad spectrum of human cancers. Thus, it is of fundamental clinical importance to understand its molecular functions and determine whether ARID1A deficiency can be exploited therapeutically. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-14-0849

    authors： Shen J,Peng Y,Wei L,Zhang W,Yang L,Lan L,Kapoor P,Ju Z,Mo Q,Shih IeM,Uray IP,Wu X,Brown PH,Shen X,Mills GB,Peng G

    更新日期：2015-07-01 00:00:00

  • Targeting the Noncoding Genome: Superenhancers Meet Their Kryptonite.

    abstract：: In this study, McKeown and colleagues carried out a genome-wide characterization and stratification of the enhancer landscape in acute myeloid leukemia (AML). The authors' analysis led to the discovery of a novel RARA superenhancer found in a subset of patients with AML, rendering these leukemia cells highly sens...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-17-0860

    authors： Wang E,Aifantis I

    更新日期：2017-10-01 00:00:00

  • HER2 signaling and resistance to the anti-EGFR monoclonal antibody cetuximab: a further step toward personalized medicine for patients with colorectal cancer.

    abstract：:Primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) drugs are clinically relevant problems in patients with metastatic colorectal carcinoma. A complex network of molecular alterations is involved in this phenomenon. Bertotti et al. report the development of serially transplantable groups of...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-11-0261

    authors： Ciardiello F,Normanno N

    更新日期：2011-11-01 00:00:00

  • Clinical Factors Predict Atezolizumab Response.

    abstract：:Researchers have presented a new model that uses six readily available clinical factors to predict whether a patient with advanced bladder cancer who has already received platinum chemotherapy will respond to treatment with the PD-L1 inhibitor atezolizumab. The results may help patients and their doctors decide how to...

    journal_title：Cancer discovery

    pub_type： 新闻

    doi：10.1158/2159-8290.CD-NB2018-018

    authors：

    更新日期：2018-04-01 00:00:00

  • Predicting cancer drug response: advancing the DREAM.

    abstract：:The DREAM challenge is a community effort to assess current capabilities in systems biology. Two recent challenges focus on cancer cell drug sensitivity and drug synergism, and highlight strengths and weaknesses of current approaches. ...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-15-0093

    authors： Altman RB

    更新日期：2015-03-01 00:00:00

  • RAS Mutations Are Not Created Equal.

    abstract：:In this issue of Cancer Discovery, Poulin and colleagues apply structural, biochemical, and biological profiling of two mutants of KRAS, one found most frequently in all cancers (G12D) and one found nearly exclusively in colorectal cancer (A146T). They provide compelling evidence that specific mutations will impart di...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-19-0406

    authors： Hobbs GA,Der CJ

    更新日期：2019-06-01 00:00:00

  • Genomic Screens Identify Genes That Regulate MHC-I Expression in DLBCL.

    abstract：:MHC-I and MHC-II regulators in lymphomas, some of which had subtype or tumor specificity, were identified. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-RW2020-178

    authors：

    更新日期：2020-12-11 00:00:00

  • Fish Reveal Origins of Melanoma.

    abstract：:A new study of zebrafish may explain why only certain skin cells grow into tumors. Besides melanoma-promoting mutations, these cells express key neural crest genes, such as crestin and sox10, that induce regression to an embryonic state. They also bear epigenetic changes that might amplify expression of these genes. ...

    journal_title：Cancer discovery

    pub_type： 新闻

    doi：10.1158/2159-8290.CD-NB2016-019

    authors： Leslie M

    更新日期：2016-04-01 00:00:00

  • Discovery of Mdm2-MdmX E3 ligase inhibitors using a cell-based ubiquitination assay.

    abstract：:E3 ubiquitin ligases are of interest as drug targets for their ability to regulate protein stability and function. The oncogene Mdm2 is an attractive E3 ligase to target, as it is the key negative regulator of the tumor suppressor p53, which controls the transcription of genes involved in cell fate. Overexpression of ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-11-0104

    authors： Herman AG,Hayano M,Poyurovsky MV,Shimada K,Skouta R,Prives C,Stockwell BR

    更新日期：2011-09-01 00:00:00

  • Relapse-Driving AML Cells Exhibit Pyrimidine-Synthesis Dependency.

    abstract：:Residual acute myeloid leukemia (AML) cells required bone marrow stromal cell-derived aspartate. ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-RW2020-118

    authors：

    更新日期：2020-10-01 00:00:00

  • STATe-of-the-art approach: using oligonucleotide decoys to target the "undruggable".

    abstract：:Sen and colleagues have shown for the first time the clinical application of an oligonucleotide decoy targeting the oncogenic transcription factor STAT3 for the treatment of head and neck tumors. Intratumoral injection of decoy effectively reduced the activity of STAT3 as evidenced by a decrease in several of its tran...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-12-0310

    authors： Koppikar P,Bromberg J

    更新日期：2012-08-01 00:00:00

  • Characterizing and Overriding the Structural Mechanism of the Quizartinib-Resistant FLT3 "Gatekeeper" F691L Mutation with PLX3397.

    abstract：UNLABELLED:Tyrosine kinase domain mutations are a common cause of acquired clinical resistance to tyrosine kinase inhibitors (TKI) used to treat cancer, including the FLT3 inhibitor quizartinib. Mutation of kinase "gatekeeper" residues, which control access to an allosteric pocket adjacent to the ATP-binding site, has ...

    journal_title：Cancer discovery

    pub_type： 杂志文章

    doi：10.1158/2159-8290.CD-15-0060

    authors： Smith CC,Zhang C,Lin KC,Lasater EA,Zhang Y,Massi E,Damon LE,Pendleton M,Bashir A,Sebra R,Perl A,Kasarskis A,Shellooe R,Tsang G,Carias H,Powell B,Burton EA,Matusow B,Zhang J,Spevak W,Ibrahim PN,Le MH,Hsu HH,H

    更新日期：2015-06-01 00:00:00

  • LXR Agonism Depletes MDSCs to Promote Antitumor Immunity.

    abstract：:LXR activation reduces immunosuppressive MDSCs to activate antitumor cytotoxic T cells. ...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-RW2018-010

    authors：

    更新日期：2018-03-01 00:00:00

  • Blood Monocyte Frequency May Be a Biomarker for Response to Anti-PD-1.

    abstract：:CD14+CD16-HLA-DRhi monocyte frequency was linked to response to anti-PD-1 in patients with melanoma. ...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-RW2018-016

    authors：

    更新日期：2018-03-01 00:00:00

  • Granule Neuron Precursor-Derived Astrocytes Promote Medulloblastoma.

    abstract：:Granule neuron precursors transdifferentiate into astrocytes in the tumor microenvironment. ...

    journal_title：Cancer discovery

    pub_type： 评论,杂志文章

    doi：10.1158/2159-8290.CD-RW2020-016

    authors：

    更新日期：2020-03-01 00:00:00

  • AMG 510 First to Inhibit "Undruggable" KRAS.

    abstract：:Amgen's novel small-molecule inhibitor AMG 510 has become the first drug to successfully target a KRAS mutation in patients, according to findings presented at the 2019 American Society of Clinical Oncology Annual Meeting. In a phase I trial, AMG 510 elicited partial responses in half of evaluable patients with KRASG1...

    journal_title：Cancer discovery

    pub_type： 新闻

    doi：10.1158/2159-8290.CD-NB2019-073

    authors：

    更新日期：2019-08-01 00:00:00