Evidence map›Paper›PMID 30804427›Full record

Observational studyProstate cancer and prostatic diseases2019

MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer.

Nicholas G Nickols, Ramin Nazarian, Shuang G Zhao, Victor Tan, Vladislav Uzunangelov, Zheng Xia, Robert Baertsch, Elad Neeman, Allen C Gao, George V Thomas and 21 more

Open access · hybridAbstract readMulticenter StudyObservational Study
PubMed Full text at PMC Publisher
In one paragraph

Observational study in Prostate cancer and prostatic diseases, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed, 1 pooled it
8.5field-weighted citation impact, top 2% 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

63 citing papers in PubMed, 1 synthesis or guideline pooled it, 93 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. Article
  5. Article
  6. Article
  7. Review
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Article
  14. Review
  15. Article
  16. Article
  17. Article
  18. Article
  19. Article
  20. Article

3 more citing papers are in PubMed but not listed here.

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

31 authors at 11 institutions in 2 countries.

Nicholas G NickolsDepartment of Radiation Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA.
Ramin NazarianDivision of Dermatology/Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Shuang G ZhaoDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.
Victor TanDepartment of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Piscatway, NJ, 08854, USA.
Vladislav UzunangelovCenter for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.
Zheng XiaDepartment of Molecular Microbiology & Immunology, Computational Biology Program, Oregon Health and Science University, Portland, OR, 97239, USA.
Robert BaertschCenter for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.
Elad NeemanDivision of Hematology-Oncology/Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Allen C GaoDepartment of Urology, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
George V ThomasDepartment of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
Lauren HowardDepartment of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA.
Amanda M De HoedtDivision of Urology, Durham Veterans Affairs Medical Center, Durham, NC, 27705, USA.
Josh StuartDepartment of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.
Theodore GoldsteinDivision of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
Kim ChiVancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Martin E GleaveVancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Julie N GraffVA Portland Health Care System, Portland and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA.
Tomasz M BeerDepartment of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.ORCID http://orcid.org/0000-0001-5600-9993
Justin M DrakeDepartment of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Piscatway, NJ, 08854, USA.
Christopher P EvansDepartment of Urology, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.
Rahul AggarwalDivision of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
Adam FoyeDivision of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
Felix Y FengDepartment of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
Eric J SmallDivision of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.
William J AronsonDepartment of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Stephen J FreedlandDivision of Urology, Durham Veterans Affairs Medical Center, Durham, NC, 27705, USA.
Owen N WitteDepartment of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Jiaoti HuangDepartment of Pathology, School of Medicine, Duke University, Durham, NC, 27710, USA.
Joshi J AlumkalDepartment of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
Robert E ReiterDepartment of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Matthew B RettigDepartment of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. mrettig@mednet.ucla.edu.
University of California, Los Angeles · USOregon Health & Science University · USUniversity of California, San Francisco · USUniversity of California, Santa Cruz · USDuke University · USRutgers, The State University of New Jersey · USUniversity of British Columbia · CAUniversity of California, Davis · USCedars-Sinai Medical Center · USDurham VA Medical Center · USUniversity of Michigan · US

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5M
Histologic and Immunohistochemical Biomarkers for Heavily Treated Metastatic Prostate Cancer.R01CA205001 · NCI · DUKE UNIVERSITY · PI HUANG, JIAOTI · 2016 to 2020
$1.3M
In Silico Screening of Alternative Polyadenylation Regulators in CancersK01LM012877 · NLM · OREGON HEALTH & SCIENCE UNIVERSITY · PI XIA, ZHENG · 2018 to 2020
$428k
NCI NIH HHS P30 CA016042NCI NIH HHS R01 CA205001NLM NIH HHS K01 LM012877
6 · The paper itself

Abstract

backgroundMetastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC.

methodsTo identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers.

resultsTranscriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.

conclusionsWe conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.

Indexed as

AgedAntineoplastic AgentsBiopsyDisease-Free SurvivalGene AmplificationGene Expression Regulation, NeoplasticHumansMaleMAP Kinase Signaling SystemMiddle AgedMitogen-Activated Protein Kinase 3Molecular Targeted TherapyPhosphorylationProspective StudiesProstateProstatic Neoplasms, Castration-ResistantAntineoplastic AgentsMAPK3 protein, humanMitogen-Activated Protein Kinase 3Protein Kinase InhibitorsPyridonesPyrimidinonestrametinib

Identifiers

PMID30804427
PMCPMC6853839
OpenAlexW2916721669

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.