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

Aged Antineoplastic Agents Biopsy Disease-Free Survival Gene Amplification Gene Expression Regulation, Neoplastic Humans MAP Kinase Signaling System / drug effects Male Middle Aged Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors Molecular Targeted Therapy / methods Phosphorylation / drug effects Prospective Studies Prostate / pathology Prostatic Neoplasms, Castration-Resistant / drug therapy Protein Kinase Inhibitors / pharmacology Pyridones / pharmacology Pyrimidinones / pharmacology RNA-Seq

Journal

Prostate cancer and prostatic diseases
ISSN: 1476-5608
Titre abrégé: Prostate Cancer Prostatic Dis
Pays: England
ID NLM: 9815755

Informations de publication

Date de publication:
12 2019
Historique:
received: 20 12 2018
accepted: 01 02 2019
revised: 29 01 2019
pubmed: 26 2 2019
medline: 7 7 2020
entrez: 27 2 2019
Statut: ppublish

Résumé

Metastatic 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. To 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. Transcriptomic 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. We 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.

Sections du résumé

BACKGROUND
Metastatic 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.
METHODS
To 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.
RESULTS
Transcriptomic 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.
CONCLUSIONS
We 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.

Identifiants

DOI: 10.1038/s41391-019-0134-5 PMID: 30804427 PMC: PMC6853839
pubmed: 30804427
doi: 10.1038/s41391-019-0134-5
pii: 10.1038/s41391-019-0134-5
pmc: PMC6853839
doi:

Substances chimiques

Antineoplastic Agents 0
Protein Kinase Inhibitors 0
Pyridones 0
Pyrimidinones 0
trametinib 33E86K87QN
MAPK3 protein, human EC 2.7.11.24
Mitogen-Activated Protein Kinase 3 EC 2.7.11.24

Types de publication

Journal Article Multicenter Study Observational Study Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

531-538

Subventions

Organisme : NLM NIH HHS
ID : K01 LM012877
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA205001
Pays : United States

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Auteurs

Nicholas G Nickols (NG)

Department of Radiation Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA.
Department of Radiation Oncology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Ramin Nazarian (R)

Division of Dermatology/Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Shuang G Zhao (SG)

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, 48109, USA.

Victor Tan (V)

Department of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Piscatway, NJ, 08854, USA.

Vladislav Uzunangelov (V)

Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.

Zheng Xia (Z)

Department of Molecular Microbiology & Immunology, Computational Biology Program, Oregon Health and Science University, Portland, OR, 97239, USA.

Robert Baertsch (R)

Center for Biomolecular Science and Engineering, Jack Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, CA, 95064, USA.

Elad Neeman (E)

Division of Hematology-Oncology/Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Allen C Gao (AC)

Department of Urology, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.

George V Thomas (GV)

Department of Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.

Lauren Howard (L)

Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, 27710, USA.

Amanda M De Hoedt (AM)

Division of Urology, Durham Veterans Affairs Medical Center, Durham, NC, 27705, USA.

Josh Stuart (J)

Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, 95064, USA.

Theodore Goldstein (T)

Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.

Kim Chi (K)

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Martin E Gleave (ME)

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

Julie N Graff (JN)

VA Portland Health Care System, Portland and Knight Cancer Institute, Oregon Health and Science University, Portland, OR, 97239, USA.

Tomasz M Beer (TM)

Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.
ORCID: 0000-0001-5600-9993

Justin M Drake (JM)

Department of Medicine, Division of Medical Oncology, Rutgers Robert Wood Johnson Medical School, Piscatway, NJ, 08854, USA.

Christopher P Evans (CP)

Department of Urology, School of Medicine, University of California Davis, Sacramento, CA, 95817, USA.

Rahul Aggarwal (R)

Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.

Adam Foye (A)

Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.

Felix Y Feng (FY)

Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.

Eric J Small (EJ)

Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, 94143, USA.

William J Aronson (WJ)

Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.
Division of Urology, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA.

Stephen J Freedland (SJ)

Division of Urology, Durham Veterans Affairs Medical Center, Durham, NC, 27705, USA.
Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.

Owen N Witte (ON)

Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Jiaoti Huang (J)

Department of Pathology, School of Medicine, Duke University, Durham, NC, 27710, USA.

Joshi J Alumkal (JJ)

Department of Medicine, Oregon Health and Science University, Portland, OR, 97239, USA.

Robert E Reiter (RE)

Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA.

Matthew B Rettig (MB)

Department of Urology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. mrettig@mednet.ucla.edu.
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, 90095, USA. mrettig@mednet.ucla.edu.
Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, 90073, USA. mrettig@mednet.ucla.edu.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Techniques d'investigation › Techniques cytologiques › Cytodiagnostic › Biopsie › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Survie sans rechute › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Phénomènes génétiques › Mutagenèse › Amplification de gène › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Système de signalisation des MAP kinases › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Mitogen-Activated Protein Kinases › Extracellular Signal-Regulated MAP Kinases › Mitogen-Activated Protein Kinase 3 › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Thérapie moléculaire ciblée › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Métabolisme › Phosphorylation › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Tissus › Glandes exocrines › Prostate › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Tumeurs prostatiques résistantes à la castration › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Pyridones › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Pyrimidinones › MEK-ERK signaling is a therapeutic target in...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › RNA-Seq › MEK-ERK signaling is a therapeutic target in...