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标题：Bromodomain inhibition overcomes treatment resistance in distinct molecular subtypes of melanoma
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作者：Altaf A. Dar ; Vladimir Bezrookove ; Mehdi Nosrati 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：34
DOI：10.1073/pnas.2206824119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance Resistance to targeted and immunotherapeutic agents has emerged as a critical impediment to melanoma therapy. This study identifies the bromosporine/cobimetinib combination as a therapeutic strategy with broad-based activity in multiple settings, including in both treatment-naive and resistant BRAF-mutant melanoma and in NRAS- and NF-1-mutant melanoma following resistance to PD-1 blockade. Therapy of BRAF-mutant melanoma with selective inhibitors of BRAF (BRAFi) and MEK (MEKi) represents a major clinical advance but acquired resistance to therapy has emerged as a key obstacle. To date, no clinical approaches successfully resensitize to BRAF/MEK inhibition. Here, we develop a therapeutic strategy for melanoma using bromosporine, a bromodomain inhibitor. Bromosporine (bromo) monotherapy produced significant anti-tumor effects against established melanoma cell lines and patient-derived xenografts (PDXs). Combinatorial therapy involving bromosporine and cobimetinib (bromo/cobi) showed synergistic anti-tumor effects in multiple BRAFi-resistant PDX models. The bromo/cobi combination was superior in vivo to standard BRAFi/MEKi therapy in the treatment-naive BRAF-mutant setting and to MEKi alone in the setting of immunotherapy-resistant NRAS- and NF1-mutant melanoma. RNA sequencing of xenografts treated with bromo/cobi revealed profound down-regulation of genes critical to cell division and mitotic progression. Bromo/cobi treatment resulted in marked DNA damage and cell-cycle arrest, resulting in induction of apoptosis. These studies introduce bromodomain inhibition, alone or combined with agents targeting the mitogen activated protein kinase pathway, as a rational therapeutic approach for melanoma refractory to standard targeted or immunotherapeutic approaches.
关键词：enmelanomatargeted therapybromodomain inhibitiondrug resistance