1352P Plasma metabolic signatures uncover therapeutic response and prognosis of third-generation EGFR-TKI treatment in patients with NSCLC

Advanced EGFR T790M-mutant non-small cell lung cancer (NSCLC) inevitably develops resistance to third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) therapy. Metabolic reprogramming supports EGFR-TKI resistance, while thorough metabolomics clinical studies are limited. Here, we enrolled 202 NSCLC patients from phase I and IIa clinical studies and characterized responsive metabolic features of third-generation EGFR-TKI by metabolomics, genomics and proteomics. The most frequent concurrent driver gene mutations were TP53, RB1, and PIK3CA and non-driver gene PIK3CG. Shorter progression-free survival (PFS) was related to PIK3CG (HR=3.55, P=0.06) or RB1 (HR=2.56, P=0.05) mutations and RB1 mutation was also correlated with shorter overall survival (OS) (HR=3.08, P=0.012). Baseline plasma metabolites revealed responder (R) featured by elevated glycerophospholipid and non-responder (NR) characterized by increased unsaturated fatty acids. RB1 and PIK3CG mutations were positively correlated with unsaturated fatty acids and negatively associated with glycerophospholipids. Moreover, the circulating metabolic landscape implicated two distinct metabolic subtypes (C1 and C2), suggesting that subtype C2 with worse OS was characterized by PIK3CG mutation and higher unsaturated fatty acids. Proteomics revealed C1 harbored increased levels of biosynthesis of fatty acid, fatty acid degradation, and fatty acid metabolism pathways compared to the C1 subtype. In vitro experiments, Orlistat combined with BPI-7711 had reduced IC50 (508.08nM) in comparison with BPI-7711 alone (1328nM). Furthermore, we confirmed that exogenous fatty acids promoted cell viability upon BPI-7711 treatment (IC50=1704nM versus 1328nM) through decreasing EGFR expression. Meanwhile, fatty acids downregulated FASN and upregulated CPT1A expression, which may reduce the de nove synthesis of fatty acids and influence fatty acid oxidation. This study revealed the metabolic landscape of advanced T790M-mutant NSCLC patients, providing the potential guide of personalized third-generation EGFR-TKI treatment and therapeutic target for overcoming resistance.