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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.<\/jats:p>","DOI":"10.1242\/jcs.262343","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T13:15:25Z","timestamp":1721222125000},"source":"Crossref","is-referenced-by-count":6,"title":["Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss"],"prefix":"10.1242","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0785-0860","authenticated-orcid":false,"given":"Stephanie J.","family":"Bouley","sequence":"first","affiliation":[{"name":"Geisel School of Medicine 1 Department of Molecular and Systems Biology , , Hanover, NH 03755 , USA"},{"name":"Center for Genomic Medicine, Massachusetts General Hospital 2 , Boston, MA 02114 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew V.","family":"Grassetti","sequence":"additional","affiliation":[{"name":"Geisel School of Medicine 1 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