Abstract 6723: Targeting RAS in angiosarcoma

Abstract Angiosarcomas are aggressive, rare soft tissue sarcomas that form in the lining of blood vessels. Although recurrent mutations in oncogenic drivers, including VEGFR/TIE2 (KDR, FLT4, PTPRB, and PLCG1), RAS-MAPK (KRAS, HRAS, NRAS, and NF1), and PI3K (PIK3CA and PTEN) have been identified in angiosarcomas, attempts to target these pathways using selective or multi-kinase inhibitors have generally failed to produce meaningful clinical responses. RAS proteins act as critical molecular switches that regulate cell signaling, and oncogenic mutations in RAS or VEGFR/TIE2 proteins are strongly implicated in the development of angiosarcoma. However, the mechanisms that govern these mutant pathways and the challenge of developing effective therapeutic interventions have remained elusive. A promising advancement for targeting RAS mutant tumors has been the development of the tri-complex RAS(ON) multi-selective inhibitor, RMC-7977, which simultaneously targets wild-type and mutant KRAS, NRAS, and HRAS in their active, GTP-bound state, offering a potential treatment for angiosarcoma. In this study, we identified HRAS Q61R and NRAS Q61L mutations in KU-CAS3 and KU-CAS5 angiosarcoma cell lines using Nanopore sequencing. Additionally, we detected FLT4 amplification and an NF1 frameshift deletion in HAMON cells, as well as a PTPRB deletion in ISO-HAS-B cells. Our results show that RMC-7977 and MEK1/2 inhibitor mirdametinib exhibit strong potency against angiosarcoma cell lines harboring mutations in RAS and VEGFR/TIE2 pathways. Notably, RMC-7977 showed significantly greater anti-proliferation effects in RAS wild-type and PTEN frameshift deletion AS5 angiosarcoma cells compared to midrametinib or VEGFR inhibitors. Furthermore, long-term treatment with RMC-7977 inhibited the colony-forming capacity of angiosarcoma cells. These findings suggest that RMC-7977 effectively inhibits the proliferation and survival of angiosarcoma cells. Our ongoing work involves studies to evaluate the in vivo effects of RMC-7977 on the the growth of angiosarcomas xenografts containing RAS mutations. We will also investigate the molecular mechanisms underlying oncogenic signaling to elucidate RAS dependency and strengthen the rationale for using RAS inhibitors to treat angiosarcoma. This approach aims to demonstrate that targeting RAS through RAS(ON) multi-selective inhibitors is effective, highlighting the urgent need for clinical trials to advance treatment options for angiosarcoma patients. Citation Format: Donghee Lee, Eslenur Nipa, Erin B. Dickerson, Jong Hyuk Kim. Targeting RAS in angiosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6723.