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KInome profiling of adult plexiform neurofibroma tissue before and after treatment with selumetinib: Phase 2 study of adults with inoperable plexiform neurofibroma

ABSTRACT: The MEK inhibitor selumetinib induces objective responses in children with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs). We conducted an open-label phase 2 study of selumetinib in 33 adults with PNs (NCT02407405). The objective response rate was 72.7% (24/33 patients). Median tumor volume decrease at best response was 23.6% at data cut-off with 19 patients continuing to receive study treatment. Acneiform rash was the most common adverse event (AE, 33/33 patients, 15 grade ≥2); acneiform rash and increases of ALT, AST, CPK, and lipase were the only grade 3/4 AEs to occur in more than 1 patient. Patients report improved pain levels and quality of life. Phosphorylation of ERK1/2 decreased significantly in paired biopsies (P≤0.0003) without compensatory phosphorylation of AKT1/2/3 (P =0.0697-0.9587). Selumetinib can induce sustained tumor volume decreases in adults with inoperable PNs and is well tolerated, while paired biopsies reveal novel pharmacodynamic insights. Kinase enrichment proteomic analysis was performed using patient pre-treatment/baseline and on-treatment specimens when sufficient material was obtained, with detectable on-target loss of binding of selumetinib targets MEK2 and MEK1 in treated samples.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Steven Angus

LAB HEAD: Brigitte Widemann

PROVIDER: PXD043034 | Pride | 2024-09-12

REPOSITORIES: Pride

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			Action	DRS
	2200502_SPORE_BL_25.raw	Raw
	220502_SPORE_BL_24.raw	Raw
	220502_SPORE_BL_26.raw	Raw
	220502_SPORE_BL_27.raw	Raw
	220502_SPORE_BL_29.raw	Raw

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