Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605;
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4583-4591. doi: 10.1073/pnas.1821889116. Epub 2019 Feb 19.
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. 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.
获得性 BRAF 激酶抑制剂（BRAFi）耐药是其临床获益有限的主要原因。尽管已经确定了几种获得性 BRAFi 耐药的机制，但超过 40%的黑色素瘤中获得性耐药的基础仍不清楚。我们进行了大规模的短发夹 RNA 筛选，针对 363 种表观遗传调节剂，发现增殖阻断蛋白 1（BOP1）是一个因素，其缺失导致 BRAFi 在细胞培养和小鼠中均产生耐药性。BOP1 敲低通过基于转录的机制促进 MAPK 磷酸酶 DUSP4 和 DUSP6 的下调，导致 MAPK 信号转导和 BRAFi 耐药性增加。最后，对匹配的患者来源的 BRAFi 或 BRAFi+MEKi 预处理和进展性黑色素瘤样本进行分析，发现进展性样本中 BOP1 蛋白表达降低。综上所述，我们的研究结果表明，BOP1 的缺失和由此导致的 MAPK 通路的激活是黑色素瘤对 BRAFi 获得性耐药的一种临床相关机制。
