| Autor: |
Muralidharan SV; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden., Einarsdottir BO; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden., Bhadury J; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden.; The Institute of Medical Science, Division of Stem Cell Therapy, The University of Tokyo, Tokyo, Japan., Lindberg MF; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden., Wu J; Zenith Epigenetics Ltd, Calgary, Canada., Campeau E; Zenith Epigenetics Ltd, Calgary, Canada., Bagge RO; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden., Stierner U; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and The Sahlgrenska University Hospital, Gothenburg, Sweden., Ny L; Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg and The Sahlgrenska University Hospital, Gothenburg, Sweden., Nilsson LM; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden., Nilsson JA; Sahlgrenska Cancer Center, Department of Surgery or University Hospital, Gothenburg, Sweden. |
| Abstrakt: |
Metastatic malignant melanoma continues to be a challenging disease despite clinical translation of the comprehensive understanding of driver mutations and how melanoma cells evade immune attack. In Myc-driven lymphoma, efficacy of epigenetic inhibitors of the bromodomain and extra-terminal domain (BET) family of bromodomain proteins can be enhanced by combination therapy with inhibitors of the DNA damage response kinase ATR. Whether this combination is active in solid malignancies like melanoma, and how it relates to immune therapy, has not previously investigated. To test efficacy and molecular consequences of combination therapies cultured melanoma cells were used. To assess tumor responses to therapies in vivo we use patient-derived xenografts and B6 mice transplanted with B16F10 melanoma cells. Concomitant inhibition of BET proteins and ATR of cultured melanoma cells resulted in similar effects as recently shown in lymphoma, such as induction of apoptosis and p62, implicated in autophagy, senescence-associated secretory pathway and ER stress. In vivo, apoptosis and suppression of subcutaneous growth of patient-derived melanoma and B16F10 cells were observed. Our data suggest that ATRI/BETI combination therapies are effective in melanoma. |
