| Autor: |
Karvonen H; Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland., Arjama M; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00290, Helsinki, Finland., Kaleva L; Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland., Niininen W; Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland., Barker H; Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland.; Fimlab Ltd., Tampere University Hospital, 33520, Tampere, Finland., Koivisto-Korander R; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Tapper J; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Pakarinen P; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Lassus H; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Loukovaara M; Department of Obstetrics and Gynecology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland., Bützow R; Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, PO Box 400, 00290, Helsinki, Finland., Kallioniemi O; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00290, Helsinki, Finland.; Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 171 65, Solna, Sweden., Murumägi A; Institute for Molecular Medicine Finland, FIMM, University of Helsinki, 00290, Helsinki, Finland., Ungureanu D; Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland. daniela.ungureanu@helsinki.fi.; Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, FI-00014, Helsinki, Finland. daniela.ungureanu@helsinki.fi. |
| Abstrakt: |
Glucocorticoids are routinely used in the clinic as anti-inflammatory and immunosuppressive agents as well as adjuvants during cancer treatment to mitigate the undesirable side effects of chemotherapy. However, recent studies have indicated that glucocorticoids may negatively impact the efficacy of chemotherapy by promoting tumor cell survival, heterogeneity, and metastasis. Here, we show that dexamethasone induces upregulation of ROR1 expression in ovarian cancer (OC), including platinum-resistant OC. Increased ROR1 expression resulted in elevated RhoA, YAP/TAZ, and BMI-1 levels in a panel of OC cell lines as well as primary ovarian cancer patient-derived cells, underlining the translational relevance of our studies. Importantly, dexamethasone induced differentiation of OC patient-derived cells ex vivo according to their molecular subtype and the phenotypic expression of cell differentiation markers. High-throughput drug testing with 528 emerging and clinical oncology compounds of OC cell lines and patient-derived cells revealed that dexamethasone treatment increased the sensitivity to several AKT/PI3K targeted kinase inhibitors, while significantly decreasing the efficacy of chemotherapeutics such as taxanes, as well as anti-apoptotic compounds such as SMAC mimetics. On the other hand, targeting ROR1 expression increased the efficacy of taxane drugs and SMAC mimetics, suggesting new combinatorial targeted treatments for patients with OC. |
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