Evidence map›Paper›PMID 26636651›Full record

ArticleOncotarget2015

Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model.

Mark Duquette, Peter M Sadow, Amjad Husain, Jennifer N Sims, Zeus A Antonello, Andrew H Fischer, Chen Song, Elena Castellanos-Rizaldos, G Mike Makrigiorgos, Junichi Kurebayashi and 8 more

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
3.1field-weighted citation impact, top 8% of its field
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

35 citing papers in PubMed, 47 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Article
  5. Article
  6. Article
  7. Review
  8. Review
  9. Review
  10. Review
  11. Review
  12. Review
  13. Review
  14. Article
  15. Kinase inhibitors in thyroid cancers.Endocrine oncology (Bristol, England) · 2023
    Review
  16. Review
  17. Cancers · 2021
    Article
  18. Fine-Tuning Lipid Metabolism by Targeting Mitochondria-Associated Acetyl-CoA-Carboxylase 2 inThyroid : official journal of the American Thyroid Association · 2021
    Article
  19. Article
  20. Acquired Secondary RAS Mutation in BRAFThyroid : official journal of the American Thyroid Association · 2020
    Article
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

18 authors at 9 institutions in 2 countries.

Mark DuquetteLaboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Peter M SadowDepartment of Pathology, Massachusetts General Hospital, Harvard Medical School, MA, Boston, USA.
Amjad HusainDepartment of Pathology, Center for Vascular Biology Research (CVBR), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Jennifer N SimsLaboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Zeus A AntonelloLaboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Andrew H FischerDepartment of Pathology, University of Massachusetts, Worcester, MA, USA.
Chen SongDepartment of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Elena Castellanos-RizaldosDepartment of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
G Mike MakrigiorgosDepartment of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Junichi KurebayashiDepartment of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Japan.
Vania NoseDepartment of Pathology, Massachusetts General Hospital, Harvard Medical School, MA, Boston, USA.
Paul Van HummelenCenter for Cancer Genome Discovery (CCGD), Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Roderick T BronsonRodent Histopathology Unit, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
Michelle VincoDepartment of Pathology, University of Michigan, Ann Harbor, MI, USA.
Thomas J GiordanoDepartment of Pathology, University of Michigan, Ann Harbor, MI, USA.
Dora Dias-SantagataCenter for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Pier Paolo PandolfiDivision of Cancer Genetics, Cancer Research Institute (CRI), Department of Medicine and Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Carmelo NuceraLaboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Beth Israel Deaconess Medical Center · USDana-Farber Cancer Institute · USHarvard University · USMassachusetts General Hospital · USUniversity of Michigan–Ann Arbor · USCancer Research Institute · USCenter for Vascular Biology Research · USKawasaki Medical School · JPUniversity of Massachusetts Chan Medical School · US

Funding

Training Program in Angiogenesis &InflammationT32HL007893 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI DVORAK, HAROLD FISHER · 1998 to 2017
$5.5M
BRAFV600E and VEGFR2 synergize to trigger papillary thyroid cancer progressionR01CA181183 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI NUCERA, CARMELO · 2014 to 2018
$1.8M
Metastatic protein network in BRAFV600E positive human thyroid cancersR21CA165039 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI NUCERA, CARMELO · 2012 to 2013
$407k
NCI NIH HHS 1R01CA181183-01A1NCI NIH HHS 1R21CA165039-01A1NCI NIH HHS R01 CA181183NCI NIH HHS R21 CA165039NHLBI NIH HHS T32 HL007893
6 · The paper itself

Abstract

BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAF(V600E)-positive PTC.

Indexed as

Gene DosageGenes, p16AnimalsAntineoplastic AgentsApoptosisBlotting, WesternCarcinomaCarcinoma, PapillaryCell SurvivalDisease Models, AnimalDrug Resistance, NeoplasmEnzyme-Linked Immunosorbent AssayHeterograftsHumansImmunohistochemistryIndolesAntineoplastic AgentsBRAF protein, humanIndolesMCL1 protein, humanMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins B-rafSulfonamidesVemurafenibBRAFV600E papillary thyroid cancer pre-clinical modelMCL1 and P16/CDKN2A somatic copy numbermicroenvironmentvemurafenib resisatnce

Identifiers

PMID26636651
PMCPMC4767444
OpenAlexW2185718064

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.