Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer

• Published in: European journal of cancer (1990) Vol. 49; no. 18; pp. 3821 - 3830
• Main Authors: van Soest, R.J, van Royen, M.E, de Morrée, E.S, Moll, J.M, Teubel, W, Wiemer, E.A.C, Mathijssen, R.H.J, de Wit, R, van Weerden, W.M
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01-12-2013; Elsevier
• Subjects: Abiraterone; Active Transport, Cell Nucleus - drug effects; Androgen receptor; Androstenes; Androstenols - pharmacology; Biological and medical sciences; Blotting, Western; Cabazitaxel; Castration-resistant prostate cancer; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Survival - drug effects; Docetaxel; Dose-Response Relationship, Drug; Drug Interactions; Drug resistance; Drug Resistance, Neoplasm; Enzalutamide; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hematology, Oncology and Palliative Medicine; Humans; Male; Medical sciences; Microscopy, Confocal; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Metastasis; Pharmacology. Drug treatments; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Taxoids - pharmacology; Time-Lapse Imaging; Tumors; Castration-resistant prostate cancer; Abiraterone; Docetaxel; Androgen receptor; Enzalutamide; Drug resistance; Cabazitaxel; Antineoplastic agent; Choice; Prostate disease; Antihormone; Metastasis; Cancerology; Castration; Taxane derivatives; Advanced stage; Cross resistance; Antimitotic; Male genital diseases; Drug; Treatment resistance; Urinary system disease; Antiandrogen; Malignant tumor; Castration-resistant; Prostate cancer; Cancer; Hormonal receptor
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2013.09.026

Abstract Introduction Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of cabazitaxel, abiraterone and enzalutamide. With new systemic therapies available, the optimal treatment sequence of these drugs in mCRPC becomes increasingly important. As shown recently, patients who had previously been treated with abiraterone showed impaired responses to docetaxel, suggesting clinical cross-resistance [1] . In the present study, we aimed to identify cross-resistance between taxanes (docetaxel and cabazitaxel) and the new hormonal agents abiraterone and enzalutamide. As a potential mechanism for cross-resistance, we investigated the effects on androgen receptor (AR) nuclear translocation of these compounds. Methods To identify cross-resistance, we determined the effects of docetaxel, cabazitaxel, abiraterone and enzalutamide on cell viability in prostate cancer cell lines with acquired resistance to abiraterone and enzalutamide. Time-lapse confocal microscopy was used to study the dynamics of AR nuclear translocation. Results We observed impaired efficacy of docetaxel, cabazitaxel and enzalutamide in the abiraterone-resistant cell line, compared to the non-resistant cell line, providing evidence for in vitro cross-resistance. Impaired efficacy of docetaxel, cabazitaxel and abiraterone was observed in the enzalutamide-resistant cell line. Furthermore, docetaxel and cabazitaxel inhibited AR nuclear translocation, which was also observed for abiraterone and enzalutamide. Conclusions In conclusion we found substantial preclinical evidence for cross-resistance between the taxanes docetaxel and cabazitaxel, and AR targeting agents abiraterone and enzalutamide. Since these compounds all interfere with AR-signalling, this strongly suggests a common mechanism of action, and thus a potential mechanism for cross-resistance in mCRPC.