Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res. 2019 Dec 15;79(24):6204-6214. doi: 10.1158/0008-5472.CAN-19-1415. Epub 2019 Oct 31.
Relapsed neuroblastomas are enriched with activating mutations of the RAS-MAPK signaling pathway. The MEK1/2 inhibitor trametinib delays tumor growth but does not sustain regression in neuroblastoma preclinical models. Recent studies have implicated the Hippo pathway transcriptional coactivator protein YAP1 as an additional driver of relapsed neuroblastomas, as well as a mediator of trametinib resistance in other cancers. Here, we used a highly annotated set of high-risk neuroblastoma cellular models to modulate YAP1 expression and RAS pathway activation to test whether increased YAP1 transcriptional activity is a mechanism of MEK1/2 inhibition resistance in RAS-driven neuroblastomas. In NLF (biallelic NF1 inactivation) and SK-N-AS (NRAS Q61K) cell lines, trametinib caused a near-complete translocation of YAP1 protein into the nucleus. YAP1 depletion sensitized neuroblastoma cells to trametinib, while overexpression of constitutively active YAP1 protein induced trametinib resistance. Mechanistically, significant enhancement of G-S cell-cycle arrest, mediated by depletion of MYC/MYCN and E2F transcriptional output, sensitized RAS-driven neuroblastomas to trametinib following YAP1 deletion. These findings underscore the importance of YAP activity in response to trametinib in RAS-driven neuroblastomas, as well as the potential for targeting YAP in a trametinib combination. SIGNIFICANCE: High-risk neuroblastomas with hyperactivated RAS signaling escape the selective pressure of MEK inhibition via YAP1-mediated transcriptional reprogramming and may be sensitive to combination therapies targeting both YAP1 and MEK.
复发性神经母细胞瘤中富含 RAS-MAPK 信号通路的激活突变。MEK1/2 抑制剂曲美替尼可延缓肿瘤生长，但不能维持神经母细胞瘤临床前模型的消退。最近的研究表明，Hippo 通路转录共激活蛋白 YAP1 是复发性神经母细胞瘤的另一个驱动因素，也是其他癌症中曲美替尼耐药的介质。在这里，我们使用了一组高度注释的高危神经母细胞瘤细胞模型来调节 YAP1 表达和 RAS 通路激活，以测试增加 YAP1 转录活性是否是 RAS 驱动的神经母细胞瘤中 MEK1/2 抑制耐药的机制。在 NLF（双等位基因 NF1 失活）和 SK-N-AS（NRAS Q61K）细胞系中，曲美替尼导致 YAP1 蛋白几乎完全易位到细胞核中。YAP1 缺失使神经母细胞瘤细胞对曲美替尼敏感，而过表达组成性激活的 YAP1 蛋白诱导曲美替尼耐药。从机制上讲，通过 MYC/MYCN 和 E2F 转录输出的耗竭，显著增强 G1 期细胞周期阻滞，使 RAS 驱动的神经母细胞瘤对 YAP1 缺失后的曲美替尼敏感。这些发现强调了 YAP 活性在 RAS 驱动的神经母细胞瘤中对曲美替尼反应的重要性，以及在曲美替尼联合治疗中靶向 YAP 的潜力。意义：具有过度激活 RAS 信号的高危神经母细胞瘤通过 YAP1 介导的转录重编程逃避 MEK 抑制的选择性压力，并且可能对靶向 YAP1 和 MEK 的联合治疗敏感。
