Enzalutamide (ENZA) is a frequently used therapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy-predictive serum markers. We performed comparative proteome analyses on ENZA-sensitive parental (LAPC4, DuCaP) and -resistant prostate cancer cell lines (LAPC4-ENZA, DuCaP-ENZA) using liquid chromatography tandem mass spectrometry (LC-MS/MS). The top 4 most promising candidate markers were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in pre-treatment samples of 72 ENZA-treated mCRPC patients using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)-treated mCRPC patients' baseline samples. Results were correlated with clinical and follow-up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA-sensitive and -resistant cells and our filtering methods identified 4 biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI- but not in DOC-treated patients. In LAPC4-ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA- and ABI-resistant patients and may thereby help to optimize future clinical decision-making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance. This article is protected by copyright. All rights reserved.
International journal of cancer. 2022 Jun 11 [Epub ahead of print]
Anita Csizmarik, Dávid Keresztes, Nikolett Nagy, Thilo Bracht, Barbara Sitek, Kathrin Witzke, Martin Puhr, Ilona Tornyi, József Lázár, László Takács, Gero Kramer, Sabina Sevcenco, Agnieszka Maj-Hes, Zsolt Jurányi, Boris Hadaschik, Péter Nyirády, Tibor Szarvas
Department of Urology, Semmelweis University, Budapest, Hungary., Medizinisches Proteom-Center, Ruhr University Bochum, Bochum, Germany., Department of Urology, Medical University of Innsbruck, Innsbruck, Austria., Department of Human Genetics, University of Debrecen, Debrecen, Hungary., Biosystems International Kft, Debrecen, Hungary., Department of Urology, Medical University of Vienna, Vienna, Austria., Department of Radiobiology and Diagnostic Onco-Cytogenetics, Centre of Radiotherapy, National Institute of Oncology, Budapest, Hungary., Department of Urology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.