CTPS1 promotes lung adenocarcinoma progression as a targetable vulnerability.

BACKGROUND: Cytidine triphosphate synthase 1 (CTPS1), a rate-limiting enzyme in nucleotide biosynthesis, is frequently upregulated in cancers. However, its functional role and therapeutic potential in lung adenocarcinoma (LUAD) remain poorly defined. METHODS: We integrated proteomic analyses, tissue microarrays, and functional assays to evaluate CTPS1 expression and clinical significance in LUAD. Genetic knockdown and pharmacological inhibition with the selective inhibitor STP938 assessed malignant phenotypes. The therapeutic efficacy of STP938, alone or combined with osimertinib, was evaluated in xenograft models. Integrated proteomic and transcriptomic analyses explored underlying mechanisms. RESULTS: CTPS1 was significantly upregulated in LUAD and associated with lymph node metastasis and poor overall survival (OS), serving as an independent prognostic factor. CTPS1 promoted proliferation, migration, and invasion while suppressing apoptosis. STP938 inhibited tumour growth in vitro and in vivo, and enhanced the efficacy of osimertinib in EGFR-mutant models. Multi-omics analyses identified MX1-associated interferon signalling as a downstream pathway, with MX1 expression positively correlating with CTPS1 and poor prognosis. CONCLUSIONS: CTPS1 drives LUAD progression and is linked to MX1-associated interferon signalling. Targeting CTPS1 with STP938, alone or in combination with osimertinib, represents a promising therapeutic strategy and supports CTPS1 as a targetable vulnerability in LUAD.