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Poster Presentations
Day 4, June 25（Wed.）
Room P (Maesato East, Foyer, Ocean Wing)
- 4P-AM-13
Precision Targeting of Ferroptosis in Colorectal Cancer: Sex and KRAS Mutation-Driven Metabolic Vulnerabilities and Drug Repurposing
(1Yale/HKBU, 2HKBU, 3Harvard, 4Yale, 5Columbia University)
oHong Yan1, Xinyi Shen4, Chen Chen3, Yisha Yao5, Jieqing Feng2, John Quackenbush3, Sajid Khan4, Caroline Johnson4
KRAS mutations are linked to poorer prognosis in male colorectal cancer (CRC) patients, but the sex-specific molecular mechanisms remain unclear. Our study found reduced ferroptosis in KRAS-mutant tumors in males. Using public databases and our CRC cohort, we identified sex-specific ferroptosis-associated molecular features and therapeutic opportunities. Through subsampling inference and variable importance analysis, we discovered significant gene expression differences between KRAS mutant and wild-type tumors in males, involving genes like SLC7A11 and SLC1A5. Gene regulatory network analysis highlighted enriched oxidative phosphorylation and glutathione metabolism pathways in KRAS mutant males. Random survival forest analysis revealed sex- and KRAS-specific differences in transcriptional and metabolic levels, with genes and metabolites in arginine synthesis and glutathione metabolism linked to prognosis in KRAS-mutant male tumors. Exploring drug responses using the GDSC dataset, we found that ferroptosis suppressor genes in KRAS mutant CRC cell lines were associated with resistance to cisplatin and paclitaxel in males. RSL3 combined with cisplatin or 5-FU showed enhanced efficacy, particularly in KRAS G12D mutant cell lines. This study underscores the potential for precision molecular analysis and drug repurposing in KRAS mutant CRC.