Evidence map›Paper›PMID 27648299›Full record

ArticleCell discovery2016

JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.

Bjoern Titz, Anastasia Lomova, Allison Le, Willy Hugo, Xiangju Kong, Johanna Ten Hoeve, Michael Friedman, Hubing Shi, Gatien Moriceau, Chunying Song and 7 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell discovery, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.

0numbers the graph read from it
0cells of the map it votes in
41citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

41 citing papers in PubMed.

  1. Trial
  2. Article
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  5. Multiplexed enrichment and tracking of lineages with CloneSweeper.bioRxiv : the preprint server for biology · 2026
    Article
  6. Review
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  12. Article
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  15. Article
  16. Review
  17. Article
  18. Many Distinct Ways Lead to Drug Resistance inLife (Basel, Switzerland) · 2021
    Review
  19. Advanced Melanoma: Resistance Mechanisms to Current Therapies.Hematology/oncology clinics of North America · 2021
    Review
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

17 authors.

Bjoern TitzDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Anastasia LomovaDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.ORCID 0000-0003-4713-2089
Allison LeDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Willy HugoDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.ORCID 0000-0002-1426-7190
Xiangju KongDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Johanna Ten HoeveDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Michael FriedmanDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Hubing ShiDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Gatien MoriceauDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Chunying SongDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Aayoung HongDivision of Dermatology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Mohammad AtefiDivision of Hematology-Oncology, Department of Medicine, University of California Los Angeles , Los Angeles, CA, USA.
Richard LiDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Evangelia KomisopoulouDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA.
Antoni RibasDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Division of Hematology-Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Division of Surgical-Oncology, Department of Surgery, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
Roger S LoDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Division of Dermatology, Department of Medicine, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.
Thomas G GraeberDepartment of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA; California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA.ORCID 0000-0001-8574-9181

Funding

UCLA Clinical and Translational Science InstituteUL1TR000124 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DUBINETT, STEVEN M. · 2012 to 2015
$57.0M
TARGETED COMBINATORIAL TREATMENT OF BRAF MELANOMASP01CA168585 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI DRY, SARAH M. · 2013 to 2017
$8.4M
Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistanceR01CA176111 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROGER S LO · 2013 to 2026
$5.4M
Augmenting Melanoma Response to B-Raf V600E TargetingK22CA151638 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI LO, ROGER S · 2010 to 2012
$561k
Diagnosing Emergence of Kinase Inhibitor Resistance on a MicrochipR21CA169993 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI GRAEBER, THOMAS G · 2012 to 2013
$356k
NCATS NIH HHS UL1 TR000124NCI NIH HHS K22 CA151638NCI NIH HHS P01 CA168585NCI NIH HHS R01 CA176111NCI NIH HHS R21 CA169993
6 · The paper itself

Abstract

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets.

Indexed as

BRAF inhibitionDrug resistanceEMTmelanomaphospho-proteomics

Identifiers

PMID27648299
PMCPMC5012007

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.