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TROP2 Expression Across Molecular Subtypes of Urothelial Carcinoma and Enfortumab Vedotin-resistant Cells
Jonathan Chou1, Kai Trepka2, Martin Sjöström3
1Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, USA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
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.
Insights
Sacituzumab govitecan (SG) targets TROP2 in metastatic urothelial cancer. TROP2 is highly expressed in most bladder cancer subtypes, suggesting SG efficacy across diverse patient groups, even after resistance to enfortumab vedotin (EV).
Area of Science:
- Oncology
- Translational Research
- Biomarker Discovery
Background:
- Sacituzumab govitecan (SG), a TROP2-targeting antibody-drug conjugate (ADC), is approved for refractory metastatic urothelial cancer (UC).
- Variability in TROP2 expression across bladder cancer (BC) subtypes and post-enfortumab vedotin (EV) exposure is not well understood.
- Understanding TROP2 expression is crucial for optimizing ADC therapy in metastatic BC.
Purpose of the Study:
- To investigate TROP2 expression in various bladder cancer subtypes and its correlation with NECTIN4.
- To assess TROP2 expression dynamics following enfortumab vedotin (EV) exposure.
- To evaluate the implications of TROP2 expression for sacituzumab govitecan (SG) sensitivity and treatment strategies.
Main Methods:
- Analysis of gene expression data from >1400 muscle-invasive BC patient samples across four cohorts.
- Utilized a BC tissue microarray for protein expression analysis.
- Employed CRISPR/Cas9-mediated knockdown to determine the role of TROP2 in SG sensitivity.
Main Results:
- TROP2 mRNA and protein are highly expressed in basal, luminal, and stroma-rich BC subtypes, but not in the neuroendocrine subtype.
- TROP2 mRNA levels correlate with NECTIN4 mRNA but are generally higher.
- Cells resistant to EV due to NECTIN4 downregulation retain TROP2 expression and remain sensitive to SG.
Conclusions:
- TROP2 is broadly expressed across most BC subtypes, supporting sacituzumab govitecan (SG) as a potential therapy.
- Non-overlapping resistance mechanisms exist for TROP2- and NECTIN4-targeting ADCs.
- Findings have significant implications for BC biomarker development, patient selection, and treatment sequencing.
