Impact of metabolic rewiring by KRAS mutations on plasma lipidome profiling in patients with advanced solid tumors

Abstract Purpose: To find differences in plasma lipidomic signatures between patients with advanced solid tumors harboring KRAS mutations and those with KRAS wild-type tumors. Methods: Gas chromatography coupled to quadrupole time-of-flight mass spectrometry was used to determine polar and neutral lipid levels. Data were normalized using Probabilistic Quotient Normalization. Somatic KRAS mutational status was assessed on tumor tissue. Metaboanalyst 5.0 was used to perform univariate, multivariate, and supervised analyses. Results: Thirty-seven patients were included in the study, 10 of them (27%) with KRAS-mutated tumors. The univariate analysis on polar lipids showed that patients with KRAS-mutated tumors had significantly higher levels of various lysophosphocholines (LPC) [sn1:(15:0), (18: 0), (19:0), (20:0); sn2: (14:0), (15:0), (16:0), (18:2), (19:0), (20:5)]. Levels of unsaturated fatty acids (FA) 1,13-eicosadienoic acid, adrenal acid, eicosenoic acid, SDA-iso1, and w6–DPA were significantly lower in the mutated group. Also, levels of the oxidized lipids (oxylipins) 9,10-EpOME(12), epoxy-stearic acid, x -OxoODE-iso1, 12-HETE, 15-HETE, x-HETE-iso1, x-oxoODE-iso1, were significantly lower in the group with KRAS mutation. The PLS-DA analysis also discriminated between these values between both groups. The ROC curves showed that the ratio of unsaturated FA to lysophosphocholines could predict KRAS mutation status (AUC=0.86 for the ratio 11,13-eicosadienoic/LPC sn2-20:0). Conclusion: Patients with KRAS-mutated tumors have increased plasma levels of sn2-LPC and sn1-LPC. Suggesting enhanced phospholipase 1 and 2 activity. Lower plasma levels of unsaturated FA and oxylipins in KRAS-mutant tumors suggest an enhanced consumption of FA through beta-oxidation. The ratio unsaturated FA/LPC may serve as a biomarker for KRAS mutational status prediction.