Abstract 2394: Discovery of a sex-specific metabolic phenotype in KRAS mutant colorectal cancer

Abstract KRAS mutations occur in 35-45% of all colorectal cancer (CRC) cases and are notoriously difficult to treat. It is known that anomalous metabolism is a hallmark for cancer, however the relationship between mutant KRAS and tumor metabolism in CRCs has not been fully explored. We recently showed sex-disparities in metabolism by primary tumor location, indicating the pressing need to investigate the role of biological sex in CRC. Our aim was therefore to determine whether mutant KRAS alters metabolism in a sex-specific manner. We performed non-targeted metabolomics and targeted metabolomics on stage I-III chemotherapy-naive KRAS-mutant and wild type CRC patient tumor tissues (n=197) using ultra-high-performance liquid chromatography (UHPLC) coupled to quadrupole Time-of-Flight Mass Spectrometry (QTOF-MS), and tandem MS (MS/MS). Our results showed that tumors from male patients were cystine(cysteine)-dependent, with altered glutathione (GSH) biosynthesis, transsulfuration activity, methionine metabolism, utilization of lipoxygenase pathways. Simultaneously, we performed comprehensive bioinformatic analysis of gene expression data from the Gene Expression Omnibus to further validate mutant KRAS effects on CRCs by sex. Our findings demonstrated differential expression to CBS, GPX4, GSS, ACSL4, ATF4, FTH1 and EGPR genes that are all involved in regulation of these metabolic pathways and indicate a role for ferroptosis. This data therefore validated our findings of decreased transsulfuration activity (regulated by CBS) and decreased GSH biosynthesis (regulated by GSS) in male patients; this finding was not seen in female patients. To further examine differences in ferroptosis by sex, it was seen that GPX4 was differentially expressed between KRAS mutant and wild type (p<0.05) in males, but not in females. Meanwhile, ACSL4, which appears to be a predictive marker for ferroptosis sensitivity, showed upregulated expression in males with mutant KRAS (p<0.00001). Further, KRAS mutant type linked to a poor 5-year overall survival only in male using Kaplan-Meier survival analysis. This is the first report to show unique sex-specific metabolic signatures by KRAS status in CRC patients indicating a role of decreased ferroptosis in males, thus a novel avenue for therapeutic approaches. Citation Format: Hong Yan, Yuping Cai, Xinyi Shen, Abhishek Jain, Philip B Paty, Marcus Bosenberg, Sajid A Khan, Caroline Johnson. Discovery of a sex-specific metabolic phenotype in KRAS mutant colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2394.