Sirolimus outperforms alpelisib in models of NRAS Q61R -driven vascular overgrowth.

The somatic neuroblastoma rat sarcoma virus gene p.Q61R mutation (NRAS Q61R ) occurs in patients with kaposiform lymphangiomatosis (KLA), a highly morbid and potentially fatal complex lymphatic disease. First-line therapy for KLA is mammalian target of rapamycin (mTOR) inhibitor sirolimus, although partial responses and disease progression can still occur. Alpelisib is a US Food and Drug Administration-approved p110α catalytic subunit of phosphoinositide 3-kinase α (PIK3CA) inhibitor for severe manifestations of PIK3CA-related overgrowth spectrum, and inhibits upstream of sirolimus in the phosphoinositide 3-kinase (PI3K)-mTOR pathway. Recent clinical interest in expanding the indications for alpelisib prompted this preclinical study, which aimed to determine whether alpelisib could serve as a more effective treatment for patients with KLA than sirolimus, given its upstream activity in the PI3K-mTOR signaling pathway. We compared the efficacy of sirolimus and alpelisib using NRAS Q61R endothelial cell models through in vitro assessments of pathway inhibition, cell proliferation, and migration, as well as in vivo xenograft studies. Sirolimus, at picomolar doses, outperformed alpelisib administered at micromolar concentrations across all in vitro assays and at lower doses in vivo. The use of alpelisib to treat patients with endothelial NRAS Q61R mutation may not offer any advantages over sirolimus.