Targeting RET Kinase in Neuroendocrine Prostate Cancer.

Animals Carcinoma, Neuroendocrine / drug therapy Cell Line, Tumor Gene Expression Regulation, Neoplastic / drug effects Gene Knockdown Techniques Heterocyclic Compounds, 4 or More Rings / administration & dosage Humans Male Mice PC-3 Cells Phosphorylation Prostatic Neoplasms / drug therapy Proteomics / methods Proto-Oncogene Proteins c-ret / genetics Receptors, Androgen / metabolism Up-Regulation / drug effects Xenograft Model Antitumor Assays

Journal

Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042

Informations de publication

Date de publication:
08 2020
Historique:
received: 23 12 2019
revised: 01 04 2020
accepted: 19 05 2020
pubmed: 29 5 2020
medline: 3 7 2021
entrez: 29 5 2020
Statut: ppublish

Résumé

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.

Identifiants

DOI: 10.1158/1541-7786.MCR-19-1245 PMID: 32461304 PMC: PMC7415621
pubmed: 32461304
pii: 1541-7786.MCR-19-1245
doi: 10.1158/1541-7786.MCR-19-1245
pmc: PMC7415621
mid: NIHMS1597949
doi:

Substances chimiques

AD80 compound 0
AR protein, human 0
Heterocyclic Compounds, 4 or More Rings 0
Receptors, Androgen 0
Proto-Oncogene Proteins c-ret EC 2.7.10.1
RET protein, human EC 2.7.10.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

1176-1188

Subventions

Organisme : NCI NIH HHS
ID : P30 CA077598
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM135141
Pays : United States
Organisme : NCI NIH HHS
ID : K99 CA218731
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008339
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA218731
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163227
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097186
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002494
Pays : United States

Informations de copyright

©2020 American Association for Cancer Research.

Références

Clin Cancer Res. 2019 Jan 1;25(1):43-51
pubmed: 30232224
Nat Rev Cancer. 2014 Mar;14(3):173-86
pubmed: 24561444
Clin Cancer Res. 2014 Jun 1;20(11):2846-50
pubmed: 24727321
Hum Mol Genet. 1993 Jul;2(7):851-6
pubmed: 8103403
Science. 2017 Jan 6;355(6320):84-88
pubmed: 28059768
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
pubmed: 9843981
Nat Med. 2016 Mar;22(3):298-305
pubmed: 26855148
Cell. 2017 Jul 27;170(3):564-576.e16
pubmed: 28753430
Ann Oncol. 2018 Aug 1;29(8):1869-1876
pubmed: 29912274
Eur Urol Oncol. 2018 Nov 30;:
pubmed: 31412002
Cytokine Growth Factor Rev. 2005 Aug-Oct;16(4-5):441-67
pubmed: 15982921
J Vis Exp. 2018 Aug 2;(138):
pubmed: 30124664
Clin Cancer Res. 2013 Jul 1;19(13):3621-30
pubmed: 23649003
Clin Cancer Res. 2017 Aug 15;23(16):4885-4896
pubmed: 28490466
J Clin Oncol. 2013 Feb 1;31(4):412-9
pubmed: 23169517
Cell. 2016 Aug 11;166(4):1041-1054
pubmed: 27499020
Nat Med. 2016 Apr;22(4):369-78
pubmed: 26928463
Sci Transl Med. 2017 Jun 14;9(394):
pubmed: 28615362
Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1643-8
pubmed: 22307624
Nucleic Acids Res. 2013 Jan;41(Database issue):D1063-9
pubmed: 23203882
Proc Natl Acad Sci U S A. 2013 Dec 3;110(49):E4762-9
pubmed: 24248375
J Clin Oncol. 2017 May 1;35(13):1403-1410
pubmed: 28447912
Science. 2017 Jan 6;355(6320):78-83
pubmed: 28059767
J Clin Oncol. 2018 Aug 20;36(24):2492-2503
pubmed: 29985747
Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):20111-6
pubmed: 24282295
Oncogene. 2014 Jul 17;33(29):3776-83
pubmed: 24037524
J Thorac Oncol. 2014 Sep;9(9):1316-23
pubmed: 25122427
Nature. 2001 May 17;411(6835):355-65
pubmed: 11357143
Eur Urol. 2019 Jun;75(6):929-937
pubmed: 30528222
Bioinformatics. 2004 Nov 22;20(17):3246-8
pubmed: 15180930
Nat Biotechnol. 2008 Dec;26(12):1367-72
pubmed: 19029910
Cancer Discov. 2018 Jul;8(7):836-849
pubmed: 29657135
Nat Methods. 2012 Jun 28;9(7):676-82
pubmed: 22743772
J Clin Oncol. 2016 Sep 1;34(25):3005-13
pubmed: 27400947
Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11428-11436
pubmed: 31061129
Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4473-E4482
pubmed: 29686080
Nat Protoc. 2016 Feb;11(2):347-58
pubmed: 26797458
Cancer Discov. 2011 Nov;1(6):487-95
pubmed: 22389870
Mol Cell Proteomics. 2014 Dec;13(12):3698-708
pubmed: 25360005
Methods Mol Biol. 2011;731:93-103
pubmed: 21516400
Clin Cancer Res. 2010 Dec 15;16(24):5936-41
pubmed: 20930041
Cancer Cell. 2016 Apr 11;29(4):536-547
pubmed: 27050099
Clin Epigenetics. 2015 Apr 03;7:40
pubmed: 25859291
Science. 2018 Oct 5;362(6410):91-95
pubmed: 30287662
Cancer Discov. 2017 Jan;7(1):54-71
pubmed: 27784708
Cancer Treat Rev. 2016 Nov;50:89-98
pubmed: 27664392
Nature. 2012 Jun 06;486(7401):80-4
pubmed: 22678283
Clin Cancer Res. 2015 Oct 15;21(20):4698-708
pubmed: 26071481
Sci Data. 2014 Sep 30;1:140035
pubmed: 25984343
Cancer Cell. 2017 Oct 9;32(4):474-489.e6
pubmed: 29017058

Auteurs

Halena R VanDeusen (HR)

Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
ORCID: 0000-0002-7950-2251

Johnny R Ramroop (JR)

Departments of Cancer Biology and Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Katherine L Morel (KL)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
ORCID: 0000-0002-7968-4032

Song Yi Bae (SY)

Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.

Anjali V Sheahan (AV)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Zoi Sychev (Z)

Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.

Nathan A Lau (NA)

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Larry C Cheng (LC)

Graduate Program in Quantitative Biomedicine, School of Graduate Studies, Rutgers University, New Brunswick, New Jersey.
ORCID: 0000-0002-6922-6433

Victor M Tan (VM)

Graduate Program in Quantitative Biomedicine, School of Graduate Studies, Rutgers University, New Brunswick, New Jersey.
ORCID: 0000-0001-5869-2773

Zhen Li (Z)

Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey.
ORCID: 0000-0003-0519-2905

Ashley Petersen (A)

Division of Biostatistics, School of Public Health, University of Minnesota-Twin Cities, Minneapolis, Minnesota.

John K Lee (JK)

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Medicine, University of Washington, Seattle, Washington.
ORCID: 0000-0002-6570-2180

Jung Wook Park (JW)

Department of Pathology, Duke School of Medicine, Duke University, Durham, North Carolina.
Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, California.
ORCID: 0000-0003-4798-9621

Rendong Yang (R)

The Hormel Institute, University of Minnesota, Austin, Minnesota.

Justin H Hwang (JH)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Ilsa Coleman (I)

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Owen N Witte (ON)

Department of Microbiology, Immunology, and Molecular Genetics, University of California-Los Angeles, Los Angeles, California.
ORCID: 0000-0003-4461-4533

Colm Morrissey (C)

Department of Urology, University of Washington, Seattle, Washington.

Eva Corey (E)

Department of Urology, University of Washington, Seattle, Washington.
ORCID: 0000-0002-9244-3807

Peter S Nelson (PS)

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Department of Medicine, University of Washington, Seattle, Washington.

Leigh Ellis (L)

Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.

Justin M Drake (JM)

Department of Pharmacology, University of Minnesota-Twin Cities, Minneapolis, Minnesota. jdrake@umn.edu.
Department of Urology, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
Masonic Cancer Center, University of Minnesota-Twin Cities, Minneapolis, Minnesota.
ORCID: 0000-0002-8329-7748

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroendocrines › Carcinome neuroendocrine › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Régulation de l'expression des gènes tumoraux › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Ciblage de gène › Techniques de knock-down de gènes › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérocycliques avec 4 noyaux ou plus › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules PC-3 › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Métabolisme › Phosphorylation › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Maladies urogénitales › Tumeurs de l'appareil urogénital › Tumeurs de l'appareil génital mâle › Tumeurs de la prostate › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Protéines proto-oncogènes c-ret › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Récepteurs cytoplasmiques et nucléaires › Récepteurs aux androgènes › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › Targeting RET Kinase in Neuroendocrine Prostate Cancer.
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › Targeting RET Kinase in Neuroendocrine Prostate Cancer.