Artikel
Enfortumab Vedotin induces a drug-tolerant persistant urothelial cancer cell state which can be targeted via BCL-XL inhibition
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Autoren
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Eduard Below
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
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E. Tan
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
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A. Stettner
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
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A. Heselich
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
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K. N. Tran
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
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D. Ralser
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany; Department of Gynecology, University Hospital Bonn, Bonn, Germany
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A. Maas
- Department of Otorhinolaryngology, University Hospital Bonn, Bonn, Germany
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J. Eckrich
- Department of Otorhinolaryngology, University Hospital Bonn, Bonn, Germany
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M. Toma
- Institute of Pathology, University Hospital Bonn, Bonn, Germany
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M. Eckstein
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
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Niklas Klümper
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany; Department of Urology, University Hospital Bonn, Bonn, Germany
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M. Hölzel
- Institute of Experimental Oncology, University Hospital Bonn, Bonn, Germany
| Veröffentlicht: | 26. März 2024 |
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Gliederung
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Introduction: Vedotin (EV), an anti-NECTIN-4 Antibody-Drug-Conjugate (ADC) delivering a spindle toxin, has been approved for patients with metastatic urothelial carcinoma (mUC). However, durable responses to EV are rare. Discovering the underlying molecular mechanisms is of utmost relevance to develop rational therapeutic strategies that can overcome specific resistance mechanisms. Here, in one unique patient case with longitudinal tumor tissue pre-EV start and post-progression there was a remarkable increase of multinucleated giant cells. Since these cells present a senescent-like morphology, we here systematically investigated the potential of senolytics to target these DTP.
Methods: We examined NECTIN-4, BCL-2, BCL-XL, MCL1 protein expression in a panel of urothelial cancer (UC) cell lines by Western blotting and flow cytometry. In addition, we performed immunohistochemical staining of BCL-XL and BCL-2 in 17 UC tissue samples. Further, the BCL-inhibitor responsiveness in combination with EV or alone was studied in vitro in three NECTIN- 4 expressing UC cell lines (RT4, CAL29, HT1376). In addition, the effect of a BCL-XL inhibitor on EV-induced DTP cells was assessed using IncuCyte Live-Cell Imaging.
Results: NECTIN-4 positive cell lines are susceptible to EV and form drug-tolerant persisters (DTP) with a multinucleated, senescent-like phenotype. BCL-XL is strongly expressed in UC: 15/17 tissue samples showed moderate to strong expression of BCL-XL, whereas all samples were BCL-2 negative. In vitro, combination of EV and the selective BCL-XL-Inhibitor A1331852 demonstrated synergistic efficacy with rapid killing of multinucleated giant cell DTP.
Conclusion: Our data highlight the novel therapeutic concept of combining EV and BCL-XL inhibition for patients with UC.
