1949PCell plasticity and taxanes resistance in metastatic prostate cancer: ESRP1 as a predictive biomarker of taxane response

Abstract Background Taxanes are the most active chemotherapeutic agents in metastatic castration-resistant prostate cancer (mCRPC), with demonstrated survival benefit. However, patients eventually develop resistance and no predictive molecular biomarkers are clinically available. This study analysed molecular changes associated with cell plasticity in CRPC-cell models resistant to docetaxel (D) and cabazitaxel (CZ), as well as in circulating tumour cells (CTCs) and tumour biopsies from patients with mCRPC treated with taxanes. Methods cDNA microarrays were performed in D and CZ-resistant (DR and CZR) DU-145 and PC-3 cell lines. Differential gene expression of a gene subset was validated by qRT-PCR and Western Blot analyses. Gene expression was evaluated in CTCs enriched samples and tumour samples from 22 and 118 patients, respectively. Results Microarrays analysis revealed a pronounced and intermediate epithelial-mesenchymal transition phenotype in DR and CZR cells, respectively. The penetrance of stem-cell-like and neuroendocrine phenotypes generated by D and CZ-resistance differed in the DR and CZR models. Gene expression changes also occurred in CTCs after taxane treatment. Low expression of ESRP1 in tumour samples predicted lower PSA-progression-free survival (PFS) in D-treated (HR 0.4, 95%CI 0.2-0.7, P  Conclusions Molecular changes associated with cell plasticity are different in D or CZ resistance. The EMT profile expression in primary tumour was differentially associated to D or CZ benefit. ESRP1 expression in tumour may be a potential predictive biomarker of different sensitivity to D and CZ. Legal entity responsible for the study Hospital Clinic de Barcelona. Funding Instituto de Salud Carlos III-Subdireccion General de Evaluacion y Fomento de la Investigacion; European Regional Development Fund (ERDF); CERCA Programme/Generalitat de Catalunya; Astellas Pharma S.A; Sanofi. Disclosure N. Jimenez: Travel / Accommodation / Expenses: Sanofi. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Janssen-Cilag; Speaker Bureau / Expert testimony: Bayer. A. Font: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Janssen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astra-Zeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas; Research grant / Funding (institution): Pierre Fabre. A. Rodriguez-Vida: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer ; Research grant / Funding (institution): Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Speaker Bureau / Expert testimony: Astra-Zeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Sanofi-Aventis; Advisory / Consultancy: Clovis. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: JohnsonJ Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astellas; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: MSD ; Advisory / Consultancy: Roche; Advisory / Consultancy: Astra-Zeneca; Speaker Bureau / Expert testimony: Asofarma. C. Suarez: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: EUSA Pharma; Advisory / Consultancy: Astellas ; Advisory / Consultancy: Novartis; Speaker Bureau / Expert testimony: Roche/Genentech; Speaker Bureau / Expert testimony: Astra-Zeneca; Travel / Accommodation / Expenses: Roche. M. Domenech: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Astellas; Travel / Accommodation / Expenses: Janssen. N. Sala-Gonzalez: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. A. Prat: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy, Speaker Bureau / Expert testimony: Nanostring; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly. M. Marin-Aguilera: Travel / Accommodation / Expenses: Bristol-Myers Squibb. B. Mellado: Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Sanofi; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy: Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Ipsen; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.