利用互斥频发突变的合成致死/致病效应靶向治疗葡萄膜黑色素瘤

Uveal melanoma is the most common primary intraocular malignancy in adults. The most frequently mutated genes that are considered to be drivers in uveal melanoma development and progression are GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. We found that these mutations correlate with each other by analyzing related publications as well as utilizing the large-scale cancer genome sequencing project The Cancer Genome Atlas (TCGA): mutations in GNAQ and GNA11 appear in a mutually exclusive manner; BAP1, SF3B1, and EIF1AX occur in a mutually exclusive manner; group1 (GNAQ and GNA11) and group 2 (BAP1, SF3B1, and EIF1AX) show co-occurrence. The mutual exclusivity between GNAQ and GNA11 is apparent because the similar functions of GNAQ and GNA11. Notably, the mechanisms underlying the mutually exclusive pattern among the mutations of BAP1, SF3B1, and EIF1AX remain unknown. Our preliminary data shows that BAP1 deletion and SF3B1 hotspot mutation induce synthetic senescence on the background of GANQ mutation: both BAP1 knockout in uveal melanoma cells with SF3B1 hotspot mutation and expression of SF3B1 hotspot mutation in uveal melanoma cells with BAP1 deficiency induce cellular senescence. Synthetic lethality/sickness has been of increasing interest as a strategy for cancer therapy, supported by major research investment. The successful example of a synthetic lethal therapy to reach the clinic is the targeting of BRCA1- or BRCA2-deficient tumor cells with PARP (poly (ADP-ribose) polymerase) inhibitors, and this potential success story creates a new paradigm for anticancer drug development. Encouraged by the discovery of the phenotype of synthetic senescence induced by BAP1 deficiency and SF3B1 mutation, we propose to explore the underlying mechanisms. The study aims to offer novel treatment approaches for uveal melanoma.

葡萄膜黑色素瘤是成年人最常见的原发性眼内恶性肿瘤。主要频发突变基因为GNAQ，GNA11，BAP1，SF3B1，和EIF1AX。这些频发突变相互关联： GNAQ突变和GNA11突变之间互斥; BAP1突变，SF3B1突变和EIF1AX突变之间互斥; 第一组突变（GNAQ和GNA11）和第二组突变（BAP1，SF3B1和EIF1AX）之间共存。BAP1，SF3B1，和EIF1AX突变之间互斥的机制目前未见报道。我们发现BAP1缺失与SF3B1突变在GNAQ突变的背景下导致合成致衰老。利用合成致死/致病效应开发靶向药物是目前抗肿瘤研究的热点。PARP抑制剂用于BRCA1/2突变的肿瘤患者就是利用合成致死的成功范例。本项目拟以频发突变的互斥模式为切入点，研究BAP1缺失与SF3B1突变合成致衰老的机制，以期为葡萄膜黑色素瘤患者提供新的治疗思路。

葡萄膜黑色素瘤是成年人最常见的原发性眼内恶性肿瘤。过半的UM患者在接受治疗后会发生转移，最常转移的部位是肝脏。对于发生了转移的UM目前没有有效的治疗药物，患者的平均存活期只有2到8个月。临床UM患者的基因测序数据显示，频发突变基因BAP1和SF3B1表现出互斥的模式，但其生物学机制并未阐明。我们的研究发现BAP1和SF3B1突变互斥的生物学机制为协同致衰老作用，即BAP1缺失和SF3B1突变引起细胞的衰老，导致在UM的发生发展过程中处于生存劣势而被淘汰。利用基因或通路的合成致死效应是目前抗肿瘤靶向药物研发的热点。最为成功的范例是PARP抑制剂被批准上市用于治疗BRCA突变的乳腺癌和卵巢癌患者。那么，BAP1和SF3B1的合成致衰老作用是否有前景成为个体化治疗的新方案，通过本课题的实施我们进行了深入的研究和探讨。BAP1缺失和SF3B1突变引起细胞DNA损伤修复功能缺陷，导致细胞对具有DNA损伤的化疗药物和靶向药物更为敏感以及细胞衰老表型。虽然，BAP1缺失和SF3B1 突变增加了p53蛋白表达，但p53通路在细胞衰老表型上只起到了微弱的作用。更为重要的是，BAP1缺失和SF3B1突变引起的细胞衰老表型不依赖GNAQ/11的突变背景，提示BAP1和SF3B1协同致衰老的作用在GNAQ/11突变和野生型的UM均有潜在的治疗价值。此外，在斑马鱼转移模型和裸鼠皮下成瘤模型，我们均发现了BAP1缺失和SF3B1突变联合的抗移植瘤转移和抗移植瘤生长的作用。我们的研究结果不仅阐明了BAP1和SF3B1突变互斥的生物学原因，而且为携带BAP1或SF3B1突变的UM患者提供了新的个体化治疗方案。