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Updated: Apr 27, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
CSNK1E/CTNNB1 are synthetic lethal to TP53 in colorectal cancer and are markers for prognosis
Khong-Loon Tiong1, Kuo-Ching Chang2, Kun-Tu Yeh3
1Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan, R.O.C.; Institute of Biomedical Informatics, National Yang-Ming University, Taipei 112, Taiwan, R.O.C.
Abstract:
Two genes are called synthetic lethal (SL) if their simultaneous mutations lead to cell death, but each individual mutation does not. Targeting SL partners of mutated cancer genes can kill cancer cells specifically, but leave normal cells intact. We present an integrated approach to uncovering SL pairs in colorectal cancer (CRC). Screening verified SL pairs using microarray gene expression data of cancerous and normal tissues, we first identified potential functionally relevant (simultaneously differentially expressed) gene pairs. From the top-ranked pairs, ~20 genes were chosen for immunohistochemistry (IHC) staining in 171 CRC patients. To find novel SL pairs, all 169 combined pairs from the individual IHC were synergistically correlated to five clinicopathological features, e.g. overall survival. Of the 11 predicted SL pairs, MSH2-POLB and CSNK1E-MYC were consistent with literature, and we validated the top two pairs, CSNK1E-TP53 and CTNNB1-TP53 using RNAi knockdown and small molecule inhibitors of CSNK1E in isogenic HCT-116 and RKO cells. Furthermore, synthetic lethality of CSNK1E and TP53 was verified in mouse model. Importantly, multivariate analysis revealed that CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A were independent prognosis markers from stage, with CSNK1E-P53 applicable to early-stage and the remaining three throughout all stages. Our findings suggest that CSNK1E is a promising target for TP53-mutant CRC patients which constitute ~40% to 50% of patients, while to date safety regarding inhibition of TP53 is controversial. Thus the integrated approach is useful in finding novel SL pairs for cancer therapeutics, and it is readily accessible and applicable to other cancers.
Insights
We identified novel synthetic lethal (SL) gene pairs in colorectal cancer (CRC) by integrating gene expression and patient data. Targeting these SL pairs, like CSNK1E-TP53, offers a promising strategy for specific cancer cell killing.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Synthetic lethality (SL) describes gene pairs where simultaneous mutations cause cell death, while individual mutations do not.
- Targeting SL partners of mutated cancer genes offers a strategy for specific cancer cell killing, sparing normal cells.
- Colorectal cancer (CRC) presents an opportunity for SL-based therapeutic strategies.
Purpose of the Study:
- To develop and apply an integrated approach for identifying novel synthetic lethal (SL) gene pairs in colorectal cancer (CRC).
- To validate potential SL pairs and assess their prognostic value in CRC patients.
- To identify potential therapeutic targets for CRC, particularly for TP53-mutant cases.
Main Methods:
- Integrated analysis of microarray gene expression data from cancerous and normal tissues to identify differentially expressed gene pairs.
- Immunohistochemistry (IHC) staining in 171 CRC patients to assess protein expression of candidate genes.
- Correlation analysis of SL pairs with clinicopathological features, including overall survival.
- Validation of top SL pairs using RNAi knockdown, small molecule inhibitors, and a mouse model.
Main Results:
- Identified 11 predicted SL pairs, with MSH2-POLB and CSNK1E-MYC consistent with existing literature.
- Validated CSNK1E-TP53 and CTNNB1-TP53 synthetic lethality in cell lines and a mouse model.
- Discovered four independent prognostic markers: CSNK1E-P53, CTNNB1-P53, MSH2-RB1, and BRCA1-WNT5A, with varying applicability across cancer stages.
Conclusions:
- CSNK1E is a potential therapeutic target for TP53-mutant CRC, a significant patient subgroup.
- The integrated approach effectively identifies novel SL pairs for cancer therapeutics and is applicable to other cancer types.
- Identified SL pairs serve as independent prognostic markers, aiding in patient stratification and treatment decisions.
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