Half of
soft-tissue sarcomas are
tumors with complex genomics, which display no specific genetic alterations and respond poorly to treatment. It is therefore necessary to find new therapeutic targets for these
sarcomas. Despite genetic heterogeneity across samples,
oncogenesis may be driven by common pathway alterations. Therefore, genomic and transcriptomic profiles of 106
sarcomas with complex genomics were analyzed to identify common pathways with altered genes. This brought out a gene belonging to the "cell cycle"
biological pathway, RCBTB1 (RCC1 And BTB Domain Containing
Protein 1), which is lost and downregulated in 62.5% of metastatic
tumors against 34% of non-metastatic
tumors. A retrospective study of three
sarcoma cohorts revealed that low RCBTB1 expression is prognostic for metastatic progression, specifically in patients that received
chemotherapy. In vitro and in vivo, RCBTB1 overexpression in
leiomyosarcoma cells specifically sensitized to
docetaxel-induced apoptosis. This was associated with increased mitotic rate in vitro and higher growth rate of xenografts. By contrast, RCBTB1 inhibition decreased cell proliferation and protected
sarcoma cells from apoptosis induced by
docetaxel. Collectively, these data evidenced that RCBTB1 is frequently deleted in
sarcomas with complex genomics and that its downregulation is associated with a higher risk of developing
metastasis for patients receiving
chemotherapy, likely due to their higher resistance to
docetaxel.