Continued Androgen Signalling Inhibition improves Cabazitaxel Efficacy in Prostate Cancer.

The androgen receptor (AR) pathway is a key driver of neoplastic behaviour in the different stages of metastatic prostate cancer (mPCa). Targeting the AR therefore remains the cornerstone for mPCa treatment. We have previously reported that activation of AR signalling affects taxane chemo-sensitivity in preclinical models of castration resistant PCa (CRPC). Here, we explored the anti-tumour efficacy of the AR targeted inhibitor enzalutamide combined with cabazitaxel.

We used the AR positive CRPC model PC346C-DCC-K to assess the in vitro and in vivo activity of combining enzalutamide with cabazitaxel. Subsequent validation studies were performed using an enzalutamide resistant VCaP model. To investigate the impact of AR signalling on cabazitaxel activity we used quantitative live-cell imaging of tubulin stabilization and apoptosis related nuclear fragmentation.

Enzalutamide strongly amplified cabazitaxel anti-tumour activity in the patient-derived xenograft models PC346C-DCC-K (median time to humane endpoint 77 versus 48 days, P<0.0001) and VCaP-Enza-B (median time to humane endpoint 80 versus 53 days, P<0.001). Although enzalutamide treatment by itself was ineffective in reducing tumour growth, it significantly suppressed AR signalling in PC346C-DCC-K tumours as shown by AR target gene expression. The addition of enzalutamide enhanced cabazitaxel induced apoptosis as shown by live-cell imaging (P<0.001).

Our study demonstrates that cabazitaxel efficacy can be improved by simultaneous blocking of AR signalling by enzalutamide, even if AR targeted treatment no longer affects tumour growth. These findings support clinical studies that combine AR targeted inhibitors with cabazitaxel in CRPC.

EBioMedicine. 2021 Nov 05 [Epub ahead of print]

Lisanne Mout, Martin E van Royen, Corrina de Ridder, Debra Stuurman, Wesley S van de Geer, Rute Marques, Stefan A J Buck, Pim J French, Harmen J G van de Werken, Ron H J Mathijssen, Ronald de Wit, Martijn P Lolkema, Wytske M van Weerden

Department of Medical Oncology Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Department of Urology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Pathology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Cancer Treatment Screening Facility Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Urology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Medical Oncology Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Cancer Computational Biology Center Erasmus MC Cancer Institute, University Medical Center, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Medical Oncology Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Cancer Treatment Screening Facility Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Department of Neurology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Urology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Cancer Computational Biology Center Erasmus MC Cancer Institute, University Medical Center, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Medical Oncology Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Department of Urology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Department of Pathology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Cancer Treatment Screening Facility Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Department of Neurology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands; Cancer Computational Biology Center Erasmus MC Cancer Institute, University Medical Center, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands., Department of Urology Erasmus University MC, Dr. Molewaterplein 40, 3015, GD, Rotterdam, the Netherlands. Electronic address: .

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