Neurofibromatosis type 1, a genetic disorder caused by germline mutations in neurofibromin (NF1), predisposes individuals to the development of tumours, and NF1 loss also occurs in several sporadic cancers. However, it is poorly understood why, on a molecular level, dysfunction or loss of NF1 increases the likelihood of cells becoming tumorous. Therefore, in this study (Bouley et al., 2024), Yolanda Sanchez and colleagues perform a high-throughput chemical genetic screen to identify compounds that are synthetic lethal with NF1 loss to elucidate potential underlying mechanisms. They identify the small molecule Y102, which they show perturbs autophagy, mitophagy and lysosome positioning in NF1-deficient U87-MG glioblastoma cells. Using a dual proteomics approach, the authors identify BLOC-one-related complex (BORC), which associates with and regulates the transport of lysosomes, as a likely target of Y102. Indeed, treatment of cells with Y102 mimics the perturbed lysosome positioning seen in cells lacking the BORC subunit BORCS6, and Y102 directly interacts with BORCS6. Furthermore, both Y102 treatment and BORCS6 knockdown result in increased expression of the cell cycle regulator p21 and increased nuclear size, which might be downstream consequences of BORC inhibition. Therefore, this study identifies BORC as a potential vulnerability in NF1-deficient tumours and uncovers a new avenue of research for the treatment of cancers driven by loss of NF1.
