MINING THE CELLMINER DATABASE TO IDENTIFY SHARED BIOMARKERS OF 5-FU AND OXALIPLATIN RESPONSE

Area of Science:

• Pharmacogenomics
• Molecular Biology
• Cancer Research

Background:

• 5-Fluorouracil (5-FU) and Oxaliplatin are standard colorectal cancer treatments.
• Drug resistance significantly limits the efficacy of these chemotherapies.
• Identifying resistance mechanisms can guide biomarker discovery and drug repurposing.

Purpose of the Study:

• To conduct an integrative pharmacogenomic analysis of colorectal cancer cell lines.
• To identify molecular determinants of sensitivity and resistance to 5-FU and Oxaliplatin.
• To explore potential therapeutic vulnerabilities and drug repurposing opportunities.

Main Methods:

• Utilized the NCI-60 cancer cell line panel via the CellMiner Database.
• Performed pathway enrichment analysis using PANTHER.
• Correlated individual drug responses with genetic variants, DNA methylation, copy number variations, and transcriptomic signatures.

Main Results:

• Genetic variants in ALDH9A1 and protein-altering variants in CAMSAP3, LUM, and LRIG2 were associated with resistance.
• DNA methylation of FERMT3 and copy number variation in COL1A1 indicated resistance mechanisms.
• Transcriptomic analysis identified cytoskeletal/adhesion genes, NT5E, and HIF1A as resistance drivers; microRNAs like let-7e, miR-30a, and miR-22 were also implicated.
• COL1A1 copy number variation correlated with statin sensitivity, suggesting repurposing potential.

Conclusions:

• ALDH9A1, FERMT3, NT5E, HIF1A, and specific microRNAs are nominated as potential resistance biomarkers.
• GRIN1, MTHFD2, and miR-7 may act as sensitizers.
• Drug repurposing opportunities, particularly with statins and kinase inhibitors, were identified to overcome resistance.
• Findings provide a framework for biomarker-guided therapy optimization and combination strategies in colorectal cancer.