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：2019
卷号：116
期号：10
页码：4583-4591
DOI：10.1073/pnas.1821889116
出版社：The National Academy of Sciences of the United States of America
摘要：Acquired resistance to BRAF kinase inhibitors (BRAFi) is the primary cause for their limited clinical benefit. Although several mechanisms of acquired BRAFi resistance have been identified, the basis for acquired resistance remains unknown in over 40% of melanomas. We performed a large-scale short-hairpin RNA screen, targeting 363 epigenetic regulators and identified Block of Proliferation 1 (BOP1) as a factor the loss of which results in resistance to BRAFi both in cell culture and in mice. BOP1 knockdown promoted down-regulation of the MAPK phosphatases DUSP4 and DUSP6 via a transcription-based mechanism, leading to increased MAPK signaling and BRAFi resistance. Finally, analysis of matched patient-derived BRAFi or BRAFi+MEKi pre- and progressed melanoma samples revealed reduced BOP1 protein expression in progressed samples. Collectively, our results demonstrate that loss of BOP1 and the resulting activation of the MAPK pathway is a clinically relevant mechanism for acquired resistance to BRAFi in melanoma.
