A c-ros oncogene 1 tyrosine-kinase-domain variant associated with a unique tyrosine-rich metabolic phenotype in glioblastoma: a case report

Glioblastoma exhibits profound metabolic plasticity, but direct links between rare receptor tyrosine kinase (RTK) alterations and atypical metabolic states remain poorly understood. It is about a 44-year-old man self-identified as being of Western European descent with a unique isocitrate dehydrogenase (IDH)–wildtype glioblastoma harboring a rare ROS1 tyrosine-kinase-domain variant (G1954E), together with phosphatase and tensin homolog (PTEN) loss and strong epidermal growth factor receptor (EGFR) expression. Multimodal nuclear magnetic resonance/magnetic resonance (PET/MR) imaging revealed low glucose uptake but high amino acid transport, and ex vivo 1 H high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) metabolomics identified a striking metabolic profile marked by extreme accumulation of free tyrosine, glutamine addiction, and elevated glycerol. We propose that (receptor tyrosine kinase–phosphoinositide 3-kinase–protein kinase B–mechanistic target of rapamycin (RTK–PI3K–AKT–mTOR) hyperactivation drives massive amino acid influx and membrane turnover, exceeding downstream metabolic capacity and generating a metabolic phenotype. This mechanism defines a distinct and previously undescribed metabolic signature in glioblastoma.