Integrated proteomic analysis identifies TYMS-dependent AMPK-mTOR signaling in pancreatic neuroendocrine tumors

While regulated TYMS expression is essential for DNA synthesis, sustained TYMS overexpression is a key biomarker for drug resistance and poor prognosis in patients with advanced solid tumors, including pancreatic neuroendocrine tumors (PanNETs). Using proteomic analysis, we observed that TYMS regulates proteins involved in energy-dependent metabolism. Further, we demonstrate that TYMS directly impacts the AMPK-mTOR signaling pathway, a critical axis governing the metabolic adaptation of cancer. TYMS inhibition activates AMPK signaling in PanNET cells, while TYMS overexpression suppresses AMPK activation and enhances mTOR signaling in PanNETs arising in TYMS-overexpressing <i>Men1</i> ^-/- null transgenic mouse model. In addition, TYMS expression positively correlates with mTOR-associated genes in patients with PanNET. TYMS levels also impact the efficacy of everolimus, an FDA-approved mTOR inhibitor for patients with PanNET, underscoring the clinical significance of our findings. In summary, our study uncovers a new role of TYMS linking nucleotide metabolism to growth signaling pathways via the regulation of the AMPK-mTOR axis.