血管肉瘤细胞的全面基因组分析揭示RAS通路的广泛激活

Angiosarcomas are a heterogeneous group of an aggressive vascular malignancies, with a 40% five-year survival rate and a median overall survival of 16 months for half of patients. These tumors exhibit a high degree of genomic complexity, encompassing a broad spectrum of cancer-related mutations, including TP53 , KDR, PTPRB, PIK3CA, NRAS, and CDKN2A . Despite recent advances in genomic and molecular profiling in angiosarcomas, the development of effective therapies targeting these genetic alterations and their downstream functional pathways has been hampered. This limitation is possibly due to incomplete molecular characterization and the scarcity of preclinical research models. Specifically, only a small number of angiosarcoma cell lines are available, and their molecular features and functional properties remain incompletely defined. This hinders the development of robust preclinical models and the discovery of reliable, effective drug targets. The aim of this study is to systematically characterize the genetic landscape of previously uncharacterized angiosarcoma cell lines to identify novel molecular targets and propose clinically relevant therapeutic strategies. First, we established comprehensive genomic profiles, including single nucleotide variants (SNVs), copy number variation (CNV), DNA methylation, and gene expression patterns, across a panel of angiosarcoma cell lines (AS5, ISO-HAS-B, HAMON, KU-CAS3, and KU-CAS5) using Whole Exome Sequencing and Oxford Nanopore sequencing. Our integrated analysis identified alterations in CDNK2A , PTPRB , and RAS , suggesting CDK4/6, TIE2/VEGFR2, and RAS/MAPK as potential molecular targets involved in the proliferation and survival of angiosarcoma cells. Through anti-cancer drug screening, we found that a RAS inhibitor RMC-7977 effectively suppressed angiosarcoma cell growth. Remarkably, RMC-7977 was effective in both RAS-mutated and wild-type angiosarcoma cells, concurrently leading to a reduction in phosphor-ERK and phosphor-S6K levels. In addition, the RAS signaling pathway was broadly activated across primary angiosarcoma patient tissues (n=13), irrespective of the RAS mutation status. These data suggest that RMC-7977 effectively targets the widespread, pathway-level activation of RAS arising from various upstream alterations in genomically complex angiosarcomas. Our ongoing work involves evaluating the in vivo efficacy of RMC-7977 in angiosarcoma xenograft models harboring both mutant and wild-type RAS. Furthermore, we will dissect the molecular mechanism underlying this broad RAS dependency by assessing the impact of RMC-7977 on activated RAS and downstream signaling, further supporting the rationale for its clinical use in angiosarcoma.