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MINING THE CELLMINER DATABASE TO IDENTIFY SHARED BIOMARKERS OF 5-FU AND OXALIPLATIN RESPONSE
1Department of Pharmacology, College of Pharmacy, Almaarif University, Ramadi, Iraq.
Background:
5-Fluorouracil and Oxaliplatin form backbone of colorectal cancer, yet resistance limits their efficacy. Understanding the molecular determinants of sensitivity and resistance may guide potential biomarker discovery and inform drug repurposing strategies.
Methods:
We performed an integrative pharmacogenomic analysis of the NCI-60 cancer cell line panel using CellMiner Database. Pathway enrichment was performed using PANTHER. Individual drug and molecular biomarker correlations were explored to identify potential therapeutic vulnerabilities and repurposing opportunities.
Results:
Genetic variants in ALDH9A1 were negatively associated with both 5-FU and Oxaliplatin. Protein function-affecting variants in CAMSAP3, LUM, and LRIG2 correlated negatively. DNA methylation of FERMT3 was negatively correlated with drug response, suggesting epigenetic silencing as a resistance mechanism. Copy number variation in COL1A1 also predicted resistance but correlated positively with statin sensitivity, highlighting repurposing potential. Transcriptomic signatures revealed cytoskeletal/adhesion genes (CNN3, ACTN1, DUSP10) as resistance markers, with pathway enrichment pointing to folate metabolism, MAPK signaling, and cytoskeletal remodeling. RNA-seq confirmed NT5E and HIF1A as resistance drivers. Several microRNAs including let-7e, miR-30a, and miR-22, were negatively correlated with drug activity, positioning them as potential biomarkers. Drug-drug correlation showed several cytotoxics positively associated with 5-FU/Oxaliplatin.
Conclusion:
This integrative analysis identify potential biomarkers associated with 5-FU and Oxaliplatin response, nominating ALDH9A1, FERMT3, NT5E, HIF1A, and specific microRNAs as resistance biomarkers, while GRIN1, MTHFD2, and miR-7 emerge as sensitizers. Importantly, repurposing opportunities were identified, with statins and kinase inhibitors showing context-dependent associations that may help overcome resistance. These findings may provide a framework for potential biomarkers guided therapy optimization and may inform rational combination strategies in colorectal cancer.
Insights
This study identifies genetic and epigenetic biomarkers for colorectal cancer drug resistance to 5-Fluorouracil and Oxaliplatin. It also reveals potential drug repurposing strategies, including statins, to overcome treatment resistance.
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.
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