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

Jonathan Chou; Kai Trepka; Martin Sjöström; Emily A Egusa; Carissa E Chu; Jun Zhu; Emily Chan; Ewan A Gibb; Michelle L Badura; Alberto Contreras-Sanz; Bradley A Stohr; Maxwell V Meng; Raj S Pruthi; Yair Lotan; Peter C Black; Sima P Porten; Vadim S Koshkin; Terence W Friedlander; Felix Y Feng

doi:10.1016/j.euo.2021.11.005

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

Eur Urol Oncol. 2022 Dec;5(6):714-718. doi: 10.1016/j.euo.2021.11.005. Epub 2022 Feb 23.

Authors

Jonathan Chou¹, Kai Trepka², Martin Sjöström³, Emily A Egusa³, Carissa E Chu⁴, Jun Zhu³, Emily Chan⁵, Ewan A Gibb⁶, Michelle L Badura³, Alberto Contreras-Sanz⁷, Bradley A Stohr⁵, Maxwell V Meng⁴, Raj S Pruthi⁴, Yair Lotan⁸, Peter C Black⁷, Sima P Porten⁴, Vadim S Koshkin⁹, Terence W Friedlander⁹, Felix Y Feng¹⁰

Affiliations

¹ 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: [email protected].
² 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.
³ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Radiation Oncology, University of California, San Francisco, CA, USA.
⁴ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Urology, University of California, San Francisco, CA, USA.
⁵ UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, CA, USA.
⁶ Decipher Biosciences, Inc., San Diego, CA, USA.
⁷ Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
⁸ Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁹ 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.
¹⁰ 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: [email protected].

Abstract

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.

Keywords: Antibody-drug conjugate; Bladder cancer; Enfortumab vedotin; Molecular subtypes; Sacituzumab govitecan; Urothelial cancer.

Publication types

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

MeSH terms

Carcinoma, Transitional Cell* / drug therapy
Carcinoma, Transitional Cell* / genetics
Cell Adhesion Molecules / genetics
Cell Adhesion Molecules / metabolism
Cell Adhesion Molecules / therapeutic use
Humans
Immunoconjugates* / therapeutic use
RNA, Messenger / therapeutic use
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / genetics
Urinary Bladder Neoplasms* / pathology

Substances

enfortumab vedotin
Immunoconjugates
Cell Adhesion Molecules
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding