Repurpose Phenformin for the Treatment of NF1-Mutant MPNST
Abstract
Loss of NF1 tumor suppressor drives hyperactivation of the RAS-RAF-MEK-ERK signaling cascade in MPNST. However, inhibition of this pathway by MEK inhibitor (MEKi) exhibits limited efficacy, probably due to incomplete ERK suppression and adaptive resistance responses. In this project, we aim to systematically characterize MEKi-induced metabolic adaption responses in NF1-mutant MPNST cells and assess the anti-tumor effects of phenformin, a mitochondrial complex I inhibitor, in combination with MEK inhibitor in MPNST. Unfortunately, we fail to detect any effects of phenformin on the response of NF1-mutant MPNST cells to MEK inhibitor, unlike in NF1-mutant melanoma cells as we previously reported. However, our metabolomics analyses reveal that MPNST cells undergo significant metabolic adaption in the pentose phosphate pathway(PPP), and suggest targeting PPP could represent a novel strategy for the treatment of NF1 mutant MPNST.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2023
- Accession Number
- AD1227966
Entities
People
- Bin Zheng
Organizations
- Massachusetts General Hospital