Abstract LB330: CWH43 as a prognostic marker and therapeutic target in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) remains a significant global health issue, particularly challenging due to the poor prognosis of its metastatic form. This highlights the critical need for novel and effective therapeutic targets to manage disease progression. A key focus of our research is the Cell Wall Biogenesis 43 C-Terminal Homolog (CWH43), which plays an essential role in GPI anchor biosynthesis and lipid remodeling, crucial for attaching membrane proteins to cell membranes. Our study aimed to clarify the function of CWH43 in CRC progression and evaluate its potential as a therapeutic target. Through an integrated bioinformatics analysis using public cancer databases, coupled with experimental validations in CRC cell models, we noted a conspicuous decrease in CWH43 mRNA levels in CRC tissues compared to normal tissue. This decrease in CWH43 expression correlated with poorer prognoses in CRC patients. In our experimental findings, we discovered that suppressing CWH43 led to increased proliferation, migration, and invasiveness of CRC cells, whereas its overexpression inhibited these processes. Notably, we observed elevated levels of CWH43 in CRC patients who showed a lower response to chemotherapy. Particularly in advanced-stage CRC patients (T4 and N2), high CWH43 expression correlated with reduced overall survival and shorter progression-free intervals, suggesting a potential association with chemotherapy resistance. In our cellular experiments, overexpression of CWH43 in CRC cells resulted in decreased sensitivity to chemotherapy drugs like CPT11, 5-FU, and oxaliplatin, which was consistent with a reduction in the expression of apoptosis-related markers. Additionally, there was a notable negative correlation between CWH43 expression and radiation sensitivity. Our Gene Set Enrichment Analysis (GSEA) revealed a significant connection between CWH43 and pathways involved in oxidative phosphorylation and fatty acid metabolism, indicating its role in regulating ferroptosis. We also demonstrated that overexpressing CWH43 in CRC cells increases the levels of multiple ferroptosis suppressors. Importantly, the use of ferroptosis inducers appeared to counteract the chemotherapy resistance influenced by CWH43. Based on these findings, we propose that CWH43 plays a role in inhibiting ferroptosis, contributing to therapeutic resistance in CRC. Therefore, targeting CWH43 could be a promising strategy for developing ferroptosis-inducing therapies, offering a new avenue for the treatment of CRC, especially in cases resistant to traditional therapies. Citation Format: Cheng-Chin Lee, Yu-Jia Chang, Chien-Yu Huang. CWH43 as a prognostic marker and therapeutic target in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB330.