TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells.

Humans Carcinoma, Transitional Cell / drug therapy Urinary Bladder Neoplasms / drug therapy Immunoconjugates / therapeutic use Cell Adhesion Molecules / genetics RNA, Messenger / therapeutic use
Antibody-drug conjugate Bladder cancer Enfortumab vedotin Molecular subtypes Sacituzumab govitecan Urothelial cancer

Journal

European urology oncology
ISSN: 2588-9311
Titre abrégé: Eur Urol Oncol
Pays: Netherlands
ID NLM: 101724904

Informations de publication

Date de publication:
12 2022
Historique:
received: 22 07 2021
revised: 06 11 2021
accepted: 17 11 2021
pubmed: 27 2 2022
medline: 17 12 2022
entrez: 26 2 2022
Statut: ppublish

Résumé

Sacituzumab govitecan (SG) is an antibody-drug conjugate (ADC) targeting TROP2, which has recently been approved for treatment-refractory metastatic urothelial cancer (UC). However, the variability of TROP2 expression across different bladder cancer (BC) subtypes, as well as after enfortumab vedotin (EV) exposure, remains unknown. Using gene expression data from four clinical cohorts with >1400 patient samples of muscle-invasive BC and a BC tissue microarray, we found that TROP2 mRNA and protein are highly expressed across basal, luminal, and stroma-rich subtypes, but depleted in the neuroendocrine subtype. In addition, TROP2 mRNA levels are correlated with NECTIN4 mRNA but are more highly expressed than NECTIN4 mRNA in patient cohorts and BC cell lines. Moreover, CRISPR/Cas9-mediated knockdown of TROP2 demonstrates that its expression is one factor governing SG sensitivity. After prolonged EV exposure, cells can downregulate NECTIN4, leading to EV resistance, but retain TROP2 expression and remain sensitive to SG, suggesting nonoverlapping resistance mechanisms to these ADCs. While our findings warrant further validation, they have significant implications for biomarker development, patient selection, and treatment sequencing in the clinic as well as clinical trial design and stratification for metastatic BC patients. PATIENT SUMMARY: In this report, we investigated the expression levels of the drug target TROP2 across different molecular subtypes of bladder cancer in multiple patient cohorts and cell lines. We found high levels of TROP2 in most subtypes except in the neuroendocrine subtype. Overall, TROP2 gene expression is higher than NECTIN4 gene expression, and cells resistant to enfortumab vedotin (EV), a NECTIN4-targeting antibody-drug conjugate, remain sensitive to sacituzumab govitecan (SG). Our findings suggest that SG may be effective across most bladder cancer subtypes, including the bladder cancers previously treated with EV.

Identifiants

DOI: 10.1016/j.euo.2021.11.005 PMID: 35216942 PMC: PMC10262920
pubmed: 35216942
pii: S2588-9311(21)00215-7
doi: 10.1016/j.euo.2021.11.005
pmc: PMC10262920
mid: NIHMS1865664
pii:
doi:

Substances chimiques

enfortumab vedotin DLE8519RWM
Immunoconjugates 0
Cell Adhesion Molecules 0
RNA, Messenger 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

714-718

Subventions

Organisme : NCI NIH HHS
ID : R01 CA235741
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM141323
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

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Auteurs

Jonathan Chou (J)

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA. Electronic address: Jonathan.Chou@ucsf.edu.

Kai Trepka (K)

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA; Medical Scientist Training Program, University of California, San Francisco, CA, USA.

Martin Sjöström (M)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Emily A Egusa (EA)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Carissa E Chu (CE)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.

Jun Zhu (J)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Emily Chan (E)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USA.

Ewan A Gibb (EA)

Decipher Biosciences, Inc., San Diego, CA, USA.

Michelle L Badura (ML)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA.

Alberto Contreras-Sanz (A)

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

Bradley A Stohr (BA)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USA.

Maxwell V Meng (MV)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.

Raj S Pruthi (RS)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.

Yair Lotan (Y)

Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Peter C Black (PC)

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.

Sima P Porten (SP)

UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.

Vadim S Koshkin (VS)

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Terence W Friedlander (TW)

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.

Felix Y Feng (FY)

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA. Electronic address: Felix.Feng@ucsf.edu.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › TROP2 Expression Across Molecular Subtypes of...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Carcinomes › Carcinome transitionnel › TROP2 Expression Across Molecular Subtypes of...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs de la vessie urinaire › TROP2 Expression Across Molecular Subtypes of...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Immunoconjugués › TROP2 Expression Across Molecular Subtypes of...
questionsmedicales.fr › Facteurs biologiques › Antigènes › Antigènes de surface › Molécules d'adhérence cellulaire › TROP2 Expression Across Molecular Subtypes of...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN messager › TROP2 Expression Across Molecular Subtypes of...