TMT-based phosphoproteomic analysis of ALK-positive patient-derived lung cancer cell lines with GUK1 phospho-null mutation and ALK TKI treatment

The metabolic adaptations observed in cancer are widely recognized, yet the precise mechanisms of how these metabolic adjustments support tumor growth remain unclear. This study explores the impact of guanine nucleotide metabolism on cancer progression in ALK-driven lung cancer. We showed that GUK1 phosphorylation at Y74 augments guanine nucleotide synthesis and promotes tumor growth in ALK-driven lung cancer both in vitro and in vivo. Using 16-plex TMT-phosphoproteomics, we investigated the effect of the ALK tyrosine kinase inhibitor lorlatinib on patient-derived non-small cell lung cancer cell lines with and without GUK1 Y74F mutation, thus shedding light on signaling and metabolic pathways reliant on GUK1 phosphorylation in ALK-driven lung cancer cells.