Department of Molecular and Systems Biology, Geisel School of Medicine, Hanover, NH 03755, USA.
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
J Cell Sci. 2024 Aug 1;137(15). doi: 10.1242/jcs.262343. Epub 2024 Aug 14.
Neurofibromatosis type 1, a genetic disorder caused by pathogenic germline variations in NF1, predisposes individuals to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors, such as glioblastoma (GBM), melanoma, breast, ovarian and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified BLOC-one-related complex (BORC), which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that BORC might be a promising therapeutic target for NF1-deficient tumors.
神经纤维瘤病 1 型是一种遗传性疾病，由 NF1 种系变异引起，使个体易患肿瘤，包括皮肤和丛状神经纤维瘤（CNs 和 PNs）、视神经胶质瘤、星形细胞瘤、青少年髓单核细胞白血病、高级别神经胶质瘤和恶性外周神经鞘肿瘤（MPNSTs），这些肉瘤对化疗和放疗有抗性，生存预后差。NF1 的缺失也发生在散发性肿瘤中，如神经胶质瘤（GBM）、黑色素瘤、乳腺癌、卵巢癌和肺癌。我们进行了高通量筛选与 NF1 缺失具有合成致死性的化合物，鉴定出了几种先导化合物，包括小分子 Y102。用 Y102 处理细胞会扰乱 NF1 缺陷细胞中的自噬、线粒体自噬和溶酶体定位。一种双重蛋白质组学方法鉴定出 BLOC-one 相关复合物（BORC），它是溶酶体定位和运输所必需的，是 Y102 的一个潜在靶点。用 siRNA 敲低 BORC 亚基可再现用 Y102 处理观察到的表型。我们的研究结果表明，BORC 可能是 NF1 缺陷肿瘤的一个有前途的治疗靶点。
